Host-Guest Approach to Promoting Photocatalysis Based on Consecutive Photo-Induced Electron-Transfer Processes via Efficient Förster Resonance Energy Transfer.

Supramolecular artificial light-harvesting system with highly efficient host-guest energy transfer pathway provides an ideal platform for optimizing the photochemistry process. The consecutive photo-induced electron transfer (conPET) process overcomes the energy limitation of visible-light photocatalysis, but is often compromised by mismatching between the absorption of ground state dye and its radical, weakening the efficiency of photoredox reaction. By encapsulating a conPET photocatalyst rhodamine 6G into metal-organic cage, the supramolecular approach was undertaken to tackle the intrinsic difficulty of matching the light absorption of photoexcitation between rhodamine 6G and its radical. The highly efficient Förster resonance energy transfer from the photoexcited cage to rhodamine 6G forced by host-guest encapsulation facilitates the conPET process for the single-wavelength light-driven activation of aryl halides by stabilizing and accelerating the production and accumulation of the rhodamine 6G radical intermediate. The tunable and flexible nature of the supramolecular host-guest complex renders the cage-based encapsulation strategy promising for the development of ideal photocatalysts toward the better utilization of solar energy.

Determining toxicity of europium oxide nanoparticles in immune cell components and hematopoiesis in dominant organs in mice: Role of lysosomal fluid interaction.

Extensive application of rare earth element oxide nanoparticles (REE NPs) has raised a concern over the possible toxic health effects after human exposure. Once entering the body, REE NPs are primarily processed by phagocytes in particular macrophages and undergo biotic phosphate complexation in lysosomal compartment. Such biotransformation affects the target organs and in vivo fate of REE NPs after escaping the lysosomes. However, the immunomodulatory effects of intraphagolysosomal dissolved REE NPs remains insufficient. Here, europium oxide (Eu2O3) NPs were pre-incubated with phagolysosomal simulant fluid (PSF) to mimic the biotransformation of europium oxide (p-Eu2O3) NPs under acid phagolysosome conditions. We investigated the alteration in immune cell components and the hematopoiesis disturbance on adult mice after intravenous administration of Eu2O3 NPs and p-Eu2O3 NPs. Our results indicated that the liver and spleen were the main target organs for Eu2O3 NPs and p-Eu2O3 NPs. Eu2O3 NPs had a much higher accumulative potential in organs than p-Eu2O3 NPs. Eu2O3 NPs induced more alterations in immune cells in the spleen, while p-Eu2O3 NPs caused stronger response in the liver. Regarding hematopoietic disruption, Eu2O3 NPs reduced platelets (PLTs) in peripheral blood, which might be related to the inhibited erythrocyte differentiation in the spleen. By contrast, p-Eu2O3 NPs did not cause significant disturbance in peripheral PLTs. Our study demonstrated that the preincubation with PSF led to a distinct response in the immune system compared to the pristine REE NPs, suggesting that the potentially toxic effects induced by the release of NPs after phagocytosis should not be neglected, especially when evaluating the safety of NPs application in vivo.

Anti-PD-L1 antibody TQB2450 combined with tyrosine kinase receptor inhibitor AL2846 for immunotherapy-refractory advanced hepatocellular carcinoma and esophageal squamous cell carcinoma: A prospective phase 1b cohort study.

BACKGROUND: Effective systemic therapy remains limited for advanced esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC), particularly after prior failed treatment with immune checkpoint inhibitors (ICIs). Theoretically, a combination of tyrosine kinase inhibitors (TKIs) with ICIs may restore immunotherapy sensitivity. METHODS: In this phase 1b study, patients received AL2846, an antiangiogenic TKI with multiple targets (c-MET, VEGFR1, c-KIT, Axl, RET, KDR, and VEGFR3), in combination with an anti-PD-L1 antibody (TQB2450) until disease progression, intolerable toxicity, death, or discontinuation for any cause. The primary end points included overall response rate (ORR) and safety, with secondary end points encompassing progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response. RESULTS: Between November 2021 and September 2022, 18 patients with ESCC and 15 patients with HCC, whose ORR was 11.1% (95% confidence interval [CI], 3.1%-32.8%) and 0%, respectively, were enrolled. Adverse events (AEs) of any grade and treatment-related AEs were documented in 32 patients (97.0%) and 31 patients (93.9%), respectively. Grade 3 or higher AEs were observed in 10 patients (30.3%), with vomiting (6.1%) and infectious pneumonia (9.1%) being the most prevalent. Median PFS and OS values were 3.22 months (95% CI, 1.35-5.68 months) and 5.98 months (95% CI, 3.71-8.87 months), respectively, in patients with ESCC, and 5.55 months (95% CI, 2.66 months to not evaluable [NE]) and 16.72 months (95% CI, 4.86 months to NE), respectively, in patients with HCC. The DCRs were 66.7% (95% CI, 43.75%-83.72%) in patients with ESCC and 73.3% (95% CI, 48.05%-89.10%) in patients with HCC. CONCLUSIONS: Combined TQB2450 and AL2846 therapy exhibited a favorable safety profile in immunotherapy-refractory patients with advanced ESCC and HCC.

AI-assisted smartphone-based colorimetric biosensor for visualized, rapid and sensitive detection of pathogenic bacteria.

Accurate and effective detection is essential to against bacterial infection and contamination. Novel biosensors, which detect bacterial bioproducts and convert them into measurable signals, are attracting attention. We developed an artificial intelligence (AI)-assisted smartphone-based colorimetric biosensor for the visualized, rapid, sensitive detection of pathogenic bacteria by measuring the bacteria secreted hyaluronidase (HAase). The biosensor consists of the chlorophenol red-ß-D-galactopyranoside (CPRG)-loaded hyaluronic acid (HA) hydrogel as the bioreactor and the ß-galactosidase (ß-gal)-loaded agar hydrogel as the signal generator. The HAase degrades the bioreactor and subsequently determines the release of CPRG, which could further react with ß-gal to generate signal colors. The self-developed YOLOv5 algorithm was utilized to analyze the signal colors acquired by smartphone. The biosensor can provide a report within 60 min with an ultra-low limit of detection (LoD) of 10 CFU/mL and differentiate between gram-positive (G+) and gram-negative (G-) bacteria. The proposed biosensor was successfully applied in various areas, especially the evaluation of infections in clinical samples with 100% sensitivity. We believe the designed biosensor has the potential to represent a new paradigm of "ASSURED" bacterial detection, applicable for broad biomedical uses.

Cerebral cortex activation and functional connectivity during low-load resistance training with blood flow restriction: An fNIRS study.

Despite accumulating evidence that blood flow restriction (BFR) training promotes muscle hypertrophy and strength gain, the underlying neurophysiological mechanisms have rarely been explored. The primary goal of this study is to investigate characteristics of cerebral cortex activity during BFR training under different pressure intensities. 24 males participated in 30% 1RM squat exercise, changes in oxygenated hemoglobin concentration (HbO) in the primary motor cortex (M1), pre-motor cortex (PMC), supplementary motor area (SMA), and dorsolateral prefrontal cortex (DLPFC), were measured by fNIRS. The results showed that HbO increased from 0 mmHg (non-BFR) to 250 mmHg but dropped sharply under 350 mmHg pressure intensity. In addition, HbO and functional connectivity were higher in M1 and PMC-SMA than in DLPFC. Moreover, the significant interaction effect between pressure intensity and ROI for HbO revealed that the regulation of cerebral cortex during BFR training was more pronounced in M1 and PMC-SMA than in DLPFC. In conclusion, low-load resistance training with BFR triggers acute responses in the cerebral cortex, and moderate pressure intensity achieves optimal neural benefits in enhancing cortical activation. M1 and PMC-SMA play crucial roles during BFR training through activation and functional connectivity regulation.

Structural basis of human mpox viral DNA replication inhibition by brincidofovir and cidofovir.

Mpox virus has wildly spread over 108 non-endemic regions in the world since May 2022. DNA replication of mpox is performed by DNA polymerase machinery F8-A22-E4, which is known as a great drug target. Brincidofovir and cidofovir are reported to have broad-spectrum antiviral activity against poxviruses, including mpox virus in animal models. However, the molecular mechanism is not understood. Here we report cryogenic electron microscopy structures of mpox viral F8-A22-E4 in complex with a DNA duplex, or dCTP and the DNA duplex, or cidofovir diphosphate and the DNA duplex at resolution of 3.22, 2.98 and 2.79 Å, respectively. Our structural work and DNA replication inhibition assays reveal that cidofovir diphosphate is located at the dCTP binding position with a different conformation to compete with dCTP to incorporate into the DNA and inhibit DNA synthesis. Conformation of both F8-A22-E4 and DNA is changed from the pre-dNTP binding state to DNA synthesizing state after dCTP or cidofovir diphosphate is bound, suggesting a coupling mechanism. This work provides the structural basis of DNA synthesis inhibition by brincidofovir and cidofovir, providing a rational strategy for new therapeutical development for mpox virus and other pox viruses.

Association Between Exposure to Multiple Toxic Metals in Follicular Fluid and the Risk of PCOS Among Infertile Women: The Mediating Effect of Metabolic Markers.

Polycystic ovary syndrome (PCOS) severely affects women's fertility and accompanies serious metabolic disturbances, affecting 5%-20% of women of reproductive age globally. We previously found that exposure to toxic metals in the blood raised the risk of PCOS, but the association between exposure to toxic metals and the risk of PCOS in the follicular fluid, the microenvironment for oocyte growth and development in females, and its effect on metabolism has not been reported. This study aimed to evaluate the associations between the concentrations of cadmium (Cd), mercury (Hg), barium (Ba) and arsenic (As) in FF and the risk of PCOS, and to explore the mediating effect of metabolic markers in FF on the above relationship. We conducted a case-control study, including 557 women with PCOS and 651 controls. Ba, Cd, Hg and As levels in FF were measured by ICP-MS, metabolites levels in FF was measured by LC-MS/MS among 168 participants randomly selected from all the participants. Logistic regression models were used to assess the association of a single metal level with the PCOS risk, and linear regression models were used to assess the relationships of a single metal level with clinical phenotype parameters and metabolites levels. Combined effect of metals mixture levels on the risk of PCOS were assessed via weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR). Medication analysis was performed to explore the role of metabolic markers on the relationship of toxic metals levels with the risk of PCOS. The exposure levels of Cd, Hg, Ba and As in FF were all positively and significantly associated with the PCOS risk (with respect to the highest vs. lowest tertile group: OR = 1.57, 95% CI = 1.17 ~ 2.12 for Cd, OR = 1.69, 95% CI = 1.22 ~ 2.34 for Hg, OR = 1.76, 95% CI = 1.32 ~ 2.34 for Ba, OR = 1.42, 95% CI = 1.05 ~ 1.91 for As). In addition, levels of metal mixture also significantly correlated with the risk of PCOS, Cd level contributed most to it. Moreover, we observed significant positive relationships between Cd level and LH (ß = 0.048, 95% CI = 0.002 ~ 0.094), T (ß = 0.077, 95% CI = 0.029 ~ 0.125) and HOMA-IR value (ß = 0.060, 95% CI = 0.012 ~ 0.107), as well as Hg level with LH, FSH/LH ratio and TC. Furthermore, we revealed that estrone sulfate, LysoPE 22:6 and N-Undecanoylglycine were significantly and positively mediating the association between Cd level and the risk of PCOS (with mediated proportion of 0.39, 0.24 and 0.35, respectively), and between Hg level and the risk of PCOS (with mediated proportion of 0.29, 0.20 and 0.46, respectively). These highly expressed metabolites significantly enriched in the fatty acid oxidation, steroid hormone biosynthesis and glycerophospholipids metabolism, which may explain the reason why the levels of Cd and Hg in FF associated with the phenotype of PCOS. Ba and As in FF was not found the above phenomenon. Our results suggested that exposure to multiple toxic metals (Cd, Hg, Ba and As) in FF associated with the increased risk of PCOS, Cd was a major contributor. Levels of Cd and Hg in FF significantly associated with the phenotype of PCOS. The above association may result from that Cd and Hg in FF related with the disturbance of fatty acid oxidation, steroid hormone biosynthesis and the glycerophospholipids metabolism.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Research on Dynamic Response under the External Impact of Paper Honeycomb Sandwich Board.

The dynamic mechanical behavior and cushioning performance of honeycomb sandwich panels, which are extensively employed in product cushioning packaging due to their exceptional energy absorption capabilities, were examined using a combination of experimental and numerical methods. Several factors, such as maximum acceleration-static stress, cushioning coefficient-static stress, and other curves, were analyzed under various impact conditions. The simulated stress-strain, deformation modes, cushioning coefficients, and other parameters demonstrate consistency with the experimental results. The acceleration, maximum compression, and cushioning coefficient obtained from the experiment and simulation calculation were 30.68 g, 15.44 mm, and 2.65, and 31.96 g, 14.91 mm, and 2.79, respectively. The results indicate that all error values were less than 5%, confirming the precision and reliability of the model. Furthermore, the model was utilized to simulate and predict the cushioning performance of honeycomb sandwich panels with different cell structures and paper thicknesses. These results provide a solid basis for enhancing the design of subsequent honeycomb element structures.

New findings on CD16brightCD62Ldim neutrophil subtypes in sepsis-associated ARDS: an observational clinical study.

Background: The CD16brightCD62Ldim neutrophil subtype is a recently identified neutrophil subtype. The aim of this study was to evaluate changes of peripheral blood CD16brightCD62Ldim neutrophils in patients with sepsis-associated ARDS. Methods: We prospectively recruited adult patients with sepsis-associated ARDS in the intensive care unit (ICU). Patient demographic data, medical history information, and laboratory data were collected within 48 hours of enrollment, and flow cytometry was applied to analyze the CD16brightCD62Ldim neutrophil subtype in the patients' peripheral blood. Multifactor COX regression models were used to analyze factors affecting prognosis, and Spearman correlation coefficients were used to analyze clinical and laboratory indicators affecting complications of infection. Results: Of the 40 patients, 9 patients died by the 28-day follow-up, indicating a mortality rate of 22.5%. Patients in the nonsurvival group had higher CD16brightCD62Ldim neutrophil levels. Patients with sepsis-associated ARDS who had a baseline proportion of CD16brightCD62Ldim neutrophil subtypes to total neutrophils in peripheral blood >3.73% had significantly higher 28-day mortality, while patients with CD16brightCD62Ldim neutrophil subtypes counts >2.62×109/L were also associated with significantly higher 28-day mortality. The percentage of the CD16brightCD62Ldim neutrophil subtype (HR=5.305, 95% CI 1.986-14.165, p=0.001) and IL-8 (HR=3.852, 95% CI 1.561-9.508, p=0.003) were independent risk factors for the development of infectious complications in patients with sepsis-related ARDS. The percentage of CD16brightCD62Ldim neutrophil subtypes predicted an AUC of 0.806 (95% CI 0.147-0.964, P=0.003) for the development of infectious complications, and 0.742 (95% CI 0.589-0.895, P=0.029) for the prediction of death within 28 days. Conclusion: We identified for the first time that CD16brightCD62Ldim neutrophils are elevated in patients with sepsis-associated ARDS and are associated with infectious complications and poor prognosis. The percentage of CD16brightCD62Ldim neutrophil subtypes may serve as a predictor of the development of infectious complications in patients with ARDS.

WAV E3 ubiquitin ligases mediate degradation of IAA32/34 in the TMK1-mediated auxin signaling pathway during apical hook development.

Auxin regulates plant growth and development through downstream signaling pathways, including the best-known SCFTIR1/AFB-Aux/IAA-ARF pathway and several other less characterized "noncanonical" pathways. Recently, one SCFTIR1/AFB-independent noncanonical pathway, mediated by Transmembrane Kinase 1 (TMK1), was discovered through the analyses of its functions in Arabidopsis apical hook development. Asymmetric accumulation of auxin on the concave side of the apical hook triggers DAR1-catalyzed release of the C-terminal of TMK1, which migrates into the nucleus, where it phosphorylates and stabilizes IAA32/34 to inhibit cell elongation, which is essential for full apical hook formation. However, the molecular factors mediating IAA32/34 degradation have not been identified. Here, we show that proteins in the CYTOKININ INDUCED ROOT WAVING 1 (CKRW1)/WAVY GROWTH 3 (WAV3) subfamily act as E3 ubiquitin ligases to target IAA32/34 for ubiquitination and degradation, which is inhibited by TMK1c-mediated phosphorylation. This antagonistic interaction between TMK1c and CKRW1/WAV3 subfamily E3 ubiquitin ligases regulates IAA32/34 levels to control differential cell elongation along opposite sides of the apical hook.

An EEG Signature of MCH Neuron Activities Predicts Cocaine Seeking.

Background: Identifying biomarkers that predict substance use disorder (SUD) propensity may better strategize anti-addiction treatment. The melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) critically mediates interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. Methods: Surface EEG signals and real-time Ca2+ activities of LH MCH neurons (Ca2+MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. Results: An EEG waveform derivative - a modified theta-to-delta ratio (EEG Ratio) - accurately tracks real-time Ca2+MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through REMS manipulations, wakefulness, circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG Ratio suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG Ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG Ratio also exhibited advantages over conventional REMS measures for the predictions. Conclusions: The identified EEG Ratio may serve as a non-invasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker predicting drug use propensity.

An EEG Signature of MCH Neuron Activities Predicts Cocaine Seeking.

BACKGROUND: Identifying biomarkers that predict substance use disorder (SUD) propensity may better strategize anti-addiction treatment. The melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) critically mediates interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. METHODS: Surface EEG signals and real-time Ca2+ activities of LH MCH neurons (Ca2+MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. RESULTS: An EEG waveform derivative - a modified theta-to-delta ratio (EEG Ratio) - accurately tracks real-time Ca2+MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through REMS manipulations, wakefulness, circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG Ratio suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG Ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG Ratio also exhibited advantages over conventional REMS measures for the predictions. CONCLUSIONS: The identified EEG Ratio may serve as a non-invasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker predicting drug use propensity.

[Research progress in genetics of noise-induced hearing loss].

Noise-induced hearing loss（NIHL） is an acquired sensorineural hearing loss induced by long-term noise exposure. The susceptibility of exposed people may vary even in the same noise environment. With the development of sequencing techniques, genes related to oxidative stress, immunoinflammatory, ion homeostasis, energy metabolism, DNA damage repair and other mechanisms in NIHL have been reported continuously. And some genes may interact with noise exposure indexes. In this article, population studies on NIHL-related gene polymorphisms and gene-environment interactions in the past 20 years are reviewed, aimed to providing evidence for the construction of NIHL-related risk prediction models and the formulation of individualized interventions.

Experimental validation and comprehensive analysis of m6A methylation regulators in intervertebral disc degeneration subpopulation classification.

Intervertebral disc degeneration (IVDD) is one of the most prevalent causes of chronic low back pain. The role of m6A methylation modification in disc degeneration (IVDD) remains unclear. We investigated immune-related m6A methylation regulators as IVDD biomarkers through comprehensive analysis and experimental validation of m6A methylation regulators in disc degeneration. The training dataset was downloaded from the GEO database and analysed for differentially expressed m6A methylation regulators and immunological features, the differentially regulators were subsequently validated by a rat IVDD model and RT-qPCR. Further screening of key m6A methylation regulators based on machine learning and LASSO regression analysis. Thereafter, a predictive model based on key m6A methylation regulators was constructed for training sets, which was validated by validation set. IVDD patients were then clustered based on the expression of key m6A regulators, and the expression of key m6A regulators and immune infiltrates between clusters was investigated to determine immune markers in IVDD. Finally, we investigated the potential role of the immune marker in IVDD through enrichment analysis, protein-to-protein network analysis, and molecular prediction. By analysising of the training set, we revealed significant differences in gene expression of five methylation regulators including RBM15, YTHDC1, YTHDF3, HNRNPA2B1 and ALKBH5, while finding characteristic immune infiltration of differentially expressed genes, the result was validated by PCR. We then screen the differential m6A regulators in the training set and identified RBM15 and YTHDC1 as key m6A regulators. We then used RBM15 and YTHDC1 to construct a predictive model for IVDD and successfully validated it in the training set. Next, we clustered IVDD patients based on the expression of RBM15 and YTHDC1 and explored the immune infiltration characteristics between clusters as well as the expression of RBM15 and YTHDC1 in the clusters. YTHDC1 was finally identified as an immune biomarker for IVDD. We finally found that YTHDC1 may influence the immune microenvironment of IVDD through ABL1 and TXK. In summary, our results suggest that YTHDC1 is a potential biomarker for the development of IVDD and may provide new insights for the precise prevention and treatment of IVDD.

Designing a conjugate vaccine targeting Klebsiella pneumoniae ST258 and ST11.

Klebsiella pneumoniae (K. pneumoniae) is a common bacterium that can cause iatrogenic infection. Recently, the rise of antibiotic resistance among K. pneumoniae strains is one key factor associated with antibiotic treatment failure. Hencefore, there is an urgent need for effective K. pneumoniae vaccines. This study aimed to design a multi-epitope vaccine (MEV) candidate against K. pneumonia by utilizing an immunoinformatics method. In this study, we obtained 15 cytotoxic T lymphocyte epitopes, 10 helper T lymphocyte epitopes, 6 linear B-cell epitopes, and 2 conformational B-cell epitopes for further research. Then, we designed a multi-epitope vaccine composed of a total of 743 amino acids, containing the epitopes linked by GPGPG flexible links and an EAAAK linker to the Cholera Toxin Subunit B coadjuvant. The observed properties of the MEV, including non-allergenicity, high antigenicity, and hydrophilicity, are noteworthy. The improvements in the tertiary structure through structural refinement and disulfide bonding, coupled with promising molecular interactions revealed by molecular dynamics simulations with TLR4, position the MEV as a strong candidate for further investigation against K. pneumoniae.

The global burden of ischemic heart disease attributed to high fasting plasma glucose: Data from 1990 to 2019.

Background: Ischemic heart disease (IHD) is the leading cause of death worldwide. High fasting plasma glucose (FPG) is an increasing risk factor for IHD. We aimed to explore the long-term trends of high FPG-attributed IHD mortality during 1990-2019. Methods: Data were obtained from the Global Burden of Disease Study 2019 database. Deaths, disability-adjusted life-years (DALYs), the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) of IHD attributable to high FPG were estimated by sex, socio-demographic index (SDI), regions and age. Estimated annual percentage changes (EAPCs) were calculated to assess the trends of ASMR and ASDR of IHD attributable to high FPG. Results: IHD attributable to high FPG deaths increased from 1.04 million (0.62-1.63) in 1990 to 2.35 million (1.4-3.7) in 2019, and the corresponding DALYs rose from 19.82 million (12.68-29.4) to 43.3 million (27.8-64.2). In 2019, ASMR and ASDR of IHD burden attributable to high FPG were 30.45 (17.09-49.03) and 534.8 (340.7-792.2), respectively. The highest ASMR and ASDR of IHD attributable to high FPG occurred in low-middle SDI quintiles, with 39.28 (22.40-62.76) and 742.3 (461.5-1117.5), respectively, followed by low SDI quintiles and middle SDI quintiles. Males had higher ASMR and ASDR compared to females across the past 30 years. In addition, ASRs of DALYs and deaths were highest in those over 95 years old. Conclusion: High FPG-attributed IHD mortality and DALYs have increased dramatically and globally, particularly in low, low-middle SDI quintiles and among the elderly. High FPG remains a great concern on the global burden of IHD and effective prevention and interventions are urgently needed to curb the ranking IHD burden, especially in lower SDI regions.

Clinical Significance of HMGB1 and Autophagy-Related Genes in Sinonasal Inverted Papilloma.

OBJECTIVES: Sinonasal inverted papilloma (SNIP) is a noncancerous tumor that develops in the mucous membrane of the nasal sinuses. Many malignancies are tightly linked to autophagy, an intracellular self-degradation mechanism. HMGB1 has demonstrated its ability to modulate autophagy in many pathological conditions. This work investigates how HMGB1 and other genes involved in autophagy contribute to SNIP. MATERIAL AND METHODS: The study included 45 patients with SNIP and a control group consisting of 28 individuals. In each group, qPCR was employed to examine the mRNA expression levels of genes correlated with autophagy and HMGB1. HMGB1 and genes associated with autophagy were examined for protein expression levels via Western Blot and immunohistochemical staining assays. At the same time, the association between HMGB1 and genes involved in autophagy was discovered through correlation analysis. Furthermore, Krouse staging was utilized for investigating the expression levels of HMGB1 and other autophagy-related genes at various stages in clinically staged SNIP patients. RESULTS: LC3B, ATG5, and Beclin1 autophagy-related genes and HMGB1 were substantially expressed in SNIP. Additionally, there was a positive correlation between HMGB1 and these genes. During various phases of SNIP, the levels of HMGB1 expression and autophagy-related genes were notably elevated at stage T4 compared with stage T2. CONCLUSION: Clinical staging in SNIP is correlated with HMGB1 expression in conjunction with autophagy-related genes LC3B, ATG5, and Beclin1, suggesting the possibility of novel prognostic indicators. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.