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Recently optimized freeze-dried rabies vaccines (Vero cell) are promising for rabies prevention; however, comparisons of Essen 5-dose and Zagreb 4-dose regimens are needed for clinical applications. This phase III clinical trial aimed to assess the safety and immunogenicity of candidate freeze-dried rabies vaccines developed for human use by Shandong Yeedo Biotechnology (Registration No.: CTR20182016, http://www.chinadrugtrials.org.cn/index.html). In total, 40 participants in stage I and 1797 subjects in stage II with an age range of 10-60 years were recruited. Both 4-dose and 5-dose experimental vaccines were well-tolerated in stage 1, with similar overall adverse event (AE) rates. In stage 2, systemic fever (35.39%) and local pain (48.91%) were common, and the rate of Grade 3 AEs was approximately 2.5%. Rates of local reactions and unsolicited AEs differed among groups ( p  = .045 and 0.011). Immunogenicity analyses showed higher antibody levels, seroconversion rates, and pre-immune seroconversion rates in the 4-dose experimental group versus the 5-dose group ( p  < .001) on day 7 post-first dose, with similar GMCs (geometric mean concentrations) by day 14. Pre-immune negative subjects had comparable antibody levels in the 4-dose and 5-dose experimental groups, outperforming the 5-dose control group ( p  = .039). The rate difference (95% CI) for first-dose seroconversion at 14 days post-vaccination among pre-immune antibody-negative subjects indicated non-inferiority between the 5-dose experimental and control groups. Overall, the Shandong Yeedo rabies vaccine demonstrated satisfactory safety and efficacy, offering a new option for rabies prevention.

The emergence of multidrug-resistant microbial species has become a global health concern, calling for novel antimicrobial agents. Peptoids, a class of synthetic peptidomimetics with unique structural properties, exhibit antimicrobial activity against a broad-spectrum of microbes, in addition to their stability to enzymatic degradation, selectivity, and relative ease of synthesis. Thus, peptoids have great potential in combating various drug-resistant pathogenic microbes. This review provides a comprehensive analysis of the recent advances in utilizing peptoids as effective antimicrobial agents against a wide range of bacteria, fungi, viruses, and parasites. In addition, some of the synthetic strategies and antimicrobial mechanisms are discussed. The imperfections of antimicrobial peptoids and the defects in current antimicrobial peptoids research are pointed out and promising directions for future development in peptoids are highlighted, to pave the way for innovating better antimicrobial peptoids to address the challenges posed by multidrug-resistant microbial species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Insufficient research has focused on the effects of metal mixtures on children's neurodevelopment and TSH's potential mediating effect. Plasma concentrations of ten metals were measured among 2887 pregnant women in a persistent Chinese birth cohort. At age two, children's neurodevelopment was assessed using mental development indexes (MDIs) and psychomotor development indexes (PDIs), defining neurodevelopmental delay as MDI≤ 79 (cognitive delay) or PDI≤ 79 (motor delay). The associations between single and mixed metals with neurodevelopment delay risk were examined using generalized linear regression complemented by weighted quantile sum (WQS) regression. To investigate the mediated effects of infant Thyroid-Stimulating Hormone (TSH) on metal-associated neurodevelopment delay risk, mediation analyses were conducted. According to the single-metal model, V, Mn, and Pb levels are positively associated with neurodevelopment delay. The WQS model found consistent associations (Odds Ratio [OR] 1.55, 95% Confidence Interval [CI] 1.23 to 1.95), highlighting V, Mn, and Pb as the main causes of cognitive delay. Further mediation analysis revealed that the association between metals (mainly V, Mn, and Pb) and neurodevelopment delay risk is mediated by TSH, with proportions ranging from 3.18 to 10.14% (all P < 0.05). Our findings highlighted prenatal exposure to metals was associated with higher risks of neurodevelopmental delay, with TSH possibly mediating this effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The reproductive hormone homeostasis is crucial for child development. Exposure to metals during pregnancy may have adverse effects on offspring health. However, the association between prenatal exposure to metals and infant reproductive hormone levels remains unknown., Methods: This study involved 812 mother-infant pairs from Wuhan, China, assessing prenatal exposure to 13 metals in maternal plasma during early pregnancy and measuring five reproductive hormones in urine samples of one-month-old infants. Generalized linear models were employed to investigate the associations between individual metal exposures and urinary hormone levels in infants. Additionally, weighted quantile sum (WQS) regression and quantile g-computation were employed to evaluate the impact of metal mixtures., Results: Most of the detected metals in maternal plasma were associated with lower levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in infants. Each interquartile range (IQR) increase in manganese (Mn), barium (Ba), thallium (Tl), vanadium (V), cobalt (Co), nickel (Ni), and lead (Pb) was significantly associated with an approximately 9.87 % to 38.24 % decrease in FSH or LH. WQS and quantile g-computation models confirmed a significant association between prenatal metal mixtures and reduced FSH and LH in male infants, and WQS indicated a significant association between metal mixtures and decreased FSH in female infants., Conclusions: Maternal exposure to mixed metals during early pregnancy was associated with lower levels of FSH and LH in infants, suggesting that prenatal exposure to metals may disrupt the balance of infant reproductive hormones. Further research is warranted to confirm these associations and explore the underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Due to the periodic emission of pollutants, the exposure mode of contaminants in water bodies is mostly pulse exposure, and the toxic effects of fluctuating exposure on aquatic animals are not consistent with traditional toxicological experiments of constant exposure. The toxic effects of heavy metal antimony (Sb) on the swimming behavior of Pelophylax nigromaculatus tadpoles after pulse exposure (PESb) and continuous exposure (CESb) for 28 days were explored. The mechanisms were analyzed from the perspectives of tail muscle metabolism and transcriptomics. Compared to the control group, PESb and CESb decreased the average speed of P. nigromaculatus tadpoles by 25.72 % and 18.08 %, respectively. PESb and CESb led to changes in 70 and 24 metabolites of tail muscle, respectively. PESb led to alterations in metabolic pathways related to pyrimidine metabolism, arginine biosynthesis, and glycerophospholipid metabolism. In contrast, CESb altered metabolic pathways such as alanine, aspartate, and glutamate metabolism. Compared to the control, 1225 and 1139 DEGs were identified for PESb and CESb, respectively. These DEGs were mainly associated with functions such as immune response, DNA replication, protein digestion, and absorption. It can be seen that PESb and CESb can alter the metabolism and transcriptome of the tail muscle of P. nigromaculatus tadpoles, leading to differential expression of individual movements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we developed novel Agriophyllum squarrosum starch nanoparticles (ASSNPs) for the encapsulation of lycopene (LYC), aiming to enhance its stability and bioactivity under adverse environmental and digestive conditions. The small-granule starch extracted from A. squarrosum seeds was processed using ionic liquids (ILs) as an effective "green" solvent, followed by a systematic treatment involving ultrasonication and pullulanase to prepare the ASSNPs. The resulting nanoparticles exhibited small size, narrow particle size distribution, negative zeta potential, and high encapsulation efficiency of up to 64.3 %. The structures of ASSNPs were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and transmission electron microscopy. These analytical techniques confirmed the successful encapsulation of LYC and revealed increased intermolecular interactions. Stability and degradation experiments demonstrated that the retention of the LYC in the complexes was significantly higher than that of the unencapsulated LYC, highlighting the superior protective effects of ASSNPs on the storage and digestive stability of LYC. This research elucidated the structural features of the complex between ASSNPs and LYC, underscoring the potential of ASSNPs as a food-grade delivery system. This approach offers a sustainable method for enhancing the bioavailability of hydrophobic nutraceuticals., Competing Interests: Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Crowding stress is a significant welfare factor affecting aquatic animals in recirculating aquaculture systems. Little is known regarding the influence of prolonged crowding stress on the immunity of juvenile pearl gentian groupers. However, research exploring the potential mechanisms through which crowding stress affects fish immune function is limited. Therefore, this study aims to investigate the effect of crowding stress on the immune stress of the pearl gentian grouper juvenile (♀Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus) under prolonged conditions. We focused on the pearl gentian grouper juvenile and selected low- and high-density groups as the experimental breeding densities. Research shows that crowding stress increases the activities of alkaline acid plum and acid phosphatase, reduces the activities of lysozyme and immunoglobulin M content. RNA sequencing and comparative transcriptomic analyses were employed to explore changes in the gene expression of juvenile pearl gentian groupers subjected to crowding stress. Differential gene expression analyses between the low- and high-density groups identified 5777 unigenes that were differentially expressed following crowding stress, with 3216 and 2561 upregulated and downregulated, respectively. In the GO and KEGG enrichment analyses, many of the enriched signaling pathways related to genes were associated with immunity and oxidative stress. In addition, the combined analyses of enzyme activity and transcriptomics indicated that crowding stress suppressed the immune function of juvenile pearl gentian groupers, reducing their immune ability. Overall, these findings offer new insights into the molecular mechanisms underlying crowding stress tolerance in juvenile pearl gentian grouper, suggesting that the NF-κB pathway plays a crucial role in the immune response of the head kidney of the pearl gentian grouper to long-term crowding stress., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Rubia cordifolia L. has been formally included in the Chinese Pharmacopoeia and utilized for centuries as a traditional Chinese medicine. Mollugin, a quinone compound, is a major active compound extracted from Rubia cordifolia L. Mollugin was reported has multiple pharmacological activity, including anti-inflammatory, anti-tumor effects. However, the anti-inflammatory mechanism is not yet clear. In this study, we explored the anti-inflammatory activity and potential mechanism of mollugin in vitro and in vivo., Materials and Methods: We explored the mechanisms that mollugin suppressed IL-1β expression through ZFP91 using various assays, including western blot, immunofluorescence, immunoprecipitation, MTT, RT-PCR, and ELISA assays in vitro. In vivo, oral administration of DSS induced colitis in mice and intraperitoneal injection of alum induced peritonitis in mice., Results: First, the results demonstrated that mollugin dramatically suppressed IL-1β secretion through reducing ZFP91 in macrophages. Crucially, we proved that mollugin inhibited K63-linked Pro-IL-1β ubiquitination through ZFP91 and limitated Pro-IL-1β cleavage efficacy. In addition, ZFP91-mediated Caspase-8 inflammasome component expression was inhibited by mollugin. Furthermore, mollugin inhibited the assembly of the Caspase-8 inflammasome complex by downregulating ZFP91. In vivo studies further revealed that mollugin improved DSS-induced colitis and alum-induced peritonitis in mice by reducing ZFP91. Notely, mollugin significantly altered the abundance of gut flora in DSS-induced colitis mice, which in turn ameliorated the colitis., Conclusion: We present a novel finding that mollugin inhibition of ZFP91 is a crucial regulatory step, preventing undue inflammatory responses and thereby maintaining immune homeostasis. The current study offers new insight into the development of anti-inflammatory therapeutics targeting ZFP91., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale and Objectives: Patients with Hypopharyngeal Squamous Cell Carcinoma (HSCC) exhibiting lymphovascular invasion (LVI) frequently demonstrate a poor prognosis. We aim to determine whether contrast-enhanced computed tomography (CECT)-derived intratumoral and peritumoral radiomic features could predict the LVI status of HSCC patients., Materials and Methods: 166 patients with pathologically confirmed HSCC were included in this study, 47 of whom were LVI positive. Preoperative CECT data were randomly divided into a training dataset and a validation dataset in an 8:2 ratio. A total of 1648 radiomics features were extracted from the total tumor volume (GTV) and the surrounding 1- to 5-mm-wide tumor margins (labeled as Peri1V-5V). A deep learning model based on the GTV was also constructed. Radiomics nomograms were established by integrating deep learning model features and clinical features. Receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were utilized to evaluate and compare the predictive performance of all models., Results: Peri1V-Radscore showed the best prediction efficiency in the validation dataset among all peritumoral models. Among the clinical variables, the upper tumor boundaries and clinical N stage were independent predictors. Compared with the clinical predictor model, Peri1V-Radscore, deep learn model and Nomogram model can improve prediction efficiency in LVI status. Their respective AUC values were 0.94, 0.84, and 0.96. The results of DCA showed that a good net benefit could be obtained from the Peri1V-Radscore model., Conclusion: Intratumoral combined peritumoral radiomics model based on CECT can superior predict LVI status in HSCC patients and may have significant potential for future applications in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Per- and polyfluoroalkyl substances (PFASs) raise concerns due to their widespread distribution, persistence, and toxicity to humans. Current studies lack the use of exposure parameters for Chinese populations and probabilistic risk assessment (PRA) to assess health risks of PFASs. To provide a scientific basis for the standards of PFASs in drinking water in China, data on concentrations of nine PFASs in 649 drinking water samples were collected from China through literature review. The highest concentration of PFASs was 17.41 ± 20.06 ng/L for perfluorobutyric acid (PFBA). Higher concentrations of PFASs were found in the southeastern coastal and in Sichuan Province. The probability of exceeding the standardized limits for drinking water for PFOA and PFOS was 2.71 % and 0.91 %. PRA and deterministic risk assessment (DRA) were used to assess non-carcinogenic risks in different age groups and provinces. Health risks of PFASs from oral exposure notably exceeded dermal contact. The Hazard Quotient (HQ) for oral exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) exceeded the acceptable level with a certain probability. The non-carcinogenic risk of exposure to PFASs in drinking water was negligible for the majority of the Chinese population. The study indicates that China should increase research on limits of PFASs in drinking water to reduce the health risks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Mining activities have led to the persistent presence of substantial heavy metals at metallurgical sites. However, the impact of long-term and complex heavy metal pollution in metallurgical ruins on the structure and spatial shift of microbiome remains unclear. In this study, we focused on various types of metallurgical sites to uncover the occurrence of heavy metals in abandoned mines and the response patterns of microbial communities. The results indicate that mining activities have caused severe exceedances of multiple heavy metals, with As Bio , Cu Bio , and Fe Bio being the primary factors affecting community structure and function. Co-occurrence network analyses suggest that several genera, including Ellin6515, Cupriavidus, Acidobacteria genus RB41, Vicinamibacteraceae, Blastococcus, and Sphingomonas, may play significant roles in the synergistic metabolism of communities responding to Fe-Cu-As stress. Although random dispersal contributed to community migration, null models emphasized that variable selection predominates in the spatial turnover of community composition. Additionally, metagenomic prediction (PICRUSt2) identified key genes involved in stress and detoxification strategies of heavy metals. The composite heavy metal stress strengthened the relationship between network structure and the potential function of the community, along with critical ecosystem functions. Our findings demonstrated that microbial interactions were crucial for ecosystem management and the ecological consequences of heavy metal pollution remediation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hypopharyngeal squamous cell carcinoma (HSCC) is a type of head and neck tumor with malignant behavior and poor prognosis. Spatial transcriptomics is a method that spatially analyzes gene expression patterns in tissues and has been used to discover tumor microenvironment and molecular markers in various tumors. However, there are no published reports on spatial transcriptomic analysis of HSCC., Methods: In this study, spatial transcriptomic analysis was performed on tumor tissues in situ, peritumoral tissues, and lymphatic metastatic tissues of four patients with HSCC. Morphological markers, including panCK, SMA, and CD45, were used to identify epithelial, fibroblast, and immune cells, respectively. By analyzing the expression of more than 18, 000 genes within the transcriptome of all ROIs, differentially expressed genes of three cell types in different tissues were identified, and differentially expressed signaling pathways and immune infiltration were analyzed., Results: The spatial distribution of cells suggests that fibroblast cells in tumor tissues may be involved in the genesis and development of tumors, and the immune infiltration of lymphatic tumor metastasis is lower than that of tumors in situ. For epithelial cells, SLCO2A1, which is a favorable prognosis marker in head and neck squamous cell carcinoma (HNSCC), was significantly down-regulated in tumor tissues and lymphatic metastatic tissues compared with adjacent normal tissues. For immune cells, KANK3, which is a favorable prognosis markers in HNSCC, was significantly down-regulated in lymphatic metastatic tissues compared with adjacent normal tissues. For fibroblast cells, AQP1, CLEC3B and SLCO2A1, which are favorable prognosis markers in HNSCC, were significantly down-regulated in tumor tissues compared with adjacent normal tissues. ITGA8, which is a favorable prognosis markers in HNSCC, was significantly down-regulated in lymphatic metastatic tissues compared with normal lymphatic tissues. CSRP1, DES, and SLCO2A1 positively correlate with immune infiltration in HNSCC. Moreover, SLCO2A1 overexpression suppressed Fadu cells proliferation and metastasis and significantly correlated with favorable survival overcome in HSCC., Conclusions: We investigated tumor and fibroblast heterogeneity, as well as the immune microenvironment in HSCC by using spatial transcriptomics. SLCO2A1 may be a tumor suppressor gene and correlates with immune infiltration for HSCC and could serve as a potential target for its diagnosis and treatment., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Brucella, but little is known about how this process is regulated during infection. We have identified a critical role for nuclear factor kappa B (NF-κB) transcription factor regulation in glycolytic switching during Brucella infection for the first time. Chromatin immunoprecipitation with next-generation sequencing for NF-κB and DNA Pull-Down revealed two novel NF-κB-binding sites in the enhancer region of the Nitric oxide (NO)production-response regulator gene glucose-6-phosphate dehydrogenase (G6PD), which is important for the switch to glycolysis during a Brucella infection. These findings demonstrate that Brucella drives metabolic reprogramming by inhibiting host oxidative phosphorylation (OXPHOS) and enhancing its glycolysis via the NF-κB-G6PD-NO-pathway. These studies provide a theoretical basis for investigating drugs or vaccines to control Brucella colonization and induction of undulant by manipulating host metabolic patterns., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

With the rapid development of immunotherapy, therapeutic tumor vaccines, which aim to enhance the immunogenicity of tumor cells and activate the patient's immune system to kill tumor cells, as well as eliminate or inhibit tumor growth, have drawn increasing attention in the field of tumor therapy. However, due to the lack of immune cell infiltration, low immunogenicity, immune escape and other problems, the efficacy of tumor vaccine is often limited. Researchers have developed a variety of strategies to enhance tumor immune recognition, such as improving the immunogenicity of tumor antigens, selecting a suitable vaccine platform, or combining tumor vaccines with other anticancer treatments. In this review, we will deliberate on how to overcome the problem of therapeutic tumor vaccines, and discuss the up-to-date progress and achievements in the tumor vaccine development, as well as their future in cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest.

Aims: This cross-sectional study aimed to investigate the in vivo ankle kinetic alterations in patients with concomitant chronic ankle instability (CAI) and osteochondral lesion of the talus (OLT), which may offer opportunities for clinician intervention in treatment and rehabilitation., Methods: A total of 16 subjects with CAI (eight without OLT and eight with OLT) and eight healthy subjects underwent gait analysis in a stair descent setting. Inverse dynamic analysis was applied to ground reaction forces and marker trajectories using the AnyBody Modeling System. One-dimensional statistical parametric mapping was performed to compare ankle joint reaction force and joint moment curve among groups., Results: The patients with OLT showed significantly increased dorsiflexion moment in the ankle joint compared with healthy subjects during 38.2% to 40.9% of the gait cycle, and increased eversion moment in the ankle joint compared with patients without OLT during 25.5% to 27.6% of the gait cycle. Compared with healthy subjects, the patients with OLT showed increased anterior force during 42% to 43% of the gait cycle, and maximal medial force (p = 0.005, ηp2 = 0.399)., Conclusion: The patients with concomitant CAI and OLT exhibit increased dorsiflexion and eversion moment, as well as increased anterior and medial ankle joint reaction force during stair descent, compared with patients with CAI but without OLT and healthy subjects, respectively. Thus, a rehabilitative regimen targeting excessive ankle dorsiflexion and eversion moment may help to reduce ankle joint loading., Competing Interests: S. Cao reports funding from Huashan Hospital, Fudan University (Grant No. 2021QD037), related to this study., (© 2024 Cao et al.)

Resistive random access memory (RRAM) has emerged as a promising candidate for next-generation storage technologies due to its simple structure, high running speed, excellent durability, high integration density, and low power consumption. This paper focuses on the application of organic-inorganic hybrid perovskite (OIHP) materials in RRAM by introducing an innovative three-dimensional POPA modification strategy, which is realized by binding octa-amine-polyhedral oligomeric silsesquioxanes (8NH 2 -POSS) onto the side chains of poly(acrylic acid) (PAA), thereby enhancing the material's resilience under elevated temperatures and humidity conditions. POPA cross-links with perovskite grains at crystalline boundaries through multiple -NH 3 + and -C═O chemical anchoring sites on its branch chain, enhancing the grain adhesion, optimizing the film quality, and improving the cage structure distribution at the perovskite grain boundaries. The experimental results demonstrate that the POPA-modified OIHP RRAM exhibits an excellent resistance switching performance, with an optimal ON/OFF ratio of 5.0 × 10 5 s. After 150 days of environmental exposure, the ON/OFF ratio remains at 1.0 × 10 4 s. After 150 days of environmental exposure, the ON/OFF ratio remains at 1.0 × 10 5 , indicating good stability. Furthermore, the POPA modification endows the perovskite film with considerable flexibility, maintaining stable resistance switching performance under various bending radii. This study provides a vital reference for flexible, high-performance, and long-lifespan perovskite memory devices.

The identification of DNA methylation at specific sites is crucial for the early detection of cancer since DNA methylation is intimately associated to the occurrence and development of cancer. Herein, two types of sensors that can detect site-specific DNA methylation were developed to meet practical requirements using methylation sensitive restriction endonuclease and CRISPR/Cas12a. To accomplish rapid detection of target, an AciI-mediated CRISPR/Cas12a assay was developed by coupling AciI to recognize DNA methylation with Cas12a to identify site-specific DNA. Since protospacer adjacent motif (PAM)-dependent endonuclease activity and trans-cleavage activity of Cas12a, it is possible to detect site-specific DNA methylation within 2 h with high specificity and acceptable sensitivity. To satisfy the needs of trace target detection, we developed an GlaI-strand displacement amplification (SDA) assisted CRISPR/Cas12a system. The system converts double-stranded methylated DNA to abundant single-stranded by GlaI and SDA. Then, the combination of SDA and CRISPR/Cas12a enable cascades amplification of signal. The approach can therefore be used to detect methylation at different specified sites, even those without PAM, and can increase sensitivity with a detection limit down to 8.19 fM. Importantly, the assay can distinguish between colorectal cancer and precancerous tissue, as well as identify colorectal patients and healthy people. This study provides a new avenue for the development of new biosensors for methylation analysis, and the two methods devised have the potential to meet the multiple requirements of site-specific methylation testing in various clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lysosomes are pivotal in diverse physiological phenomena, encompassing autophagy, apoptosis, and cellular senescence. The demand for precise tumors treatment has led to the development of specific lysosome-targeting probes capable of elucidating lysosomal dynamics and facilitating targeted cell death. In this research, we report the synthesis and characterization of a novel benzopyrrolidinyl-substituted silicon phthalocyanine (Py-SiPc), designed for selective lysosome labeling and Fluorescence imaging-guided in vitro photodynamic therapy. Furthermore, we encapsulated Py-SiPc within a biocompatible nanocarrier, dipalmitoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE), to create water-soluble nanoparticles (DSPE@Py-SiPc). These nanoparticles exhibit exceptional lysosome labeling capabilities, as evidenced by bioimaging techniques. Upon exposure to laser irradiation, DSPE@Py-SiPc efficiently induces the production of reactive oxygen species, impairing lysosomal function and triggering lysosomal-mediated cell death. The DSPE@Py-SiPc system emerges as a promising photosensitizer for cancer therapy, heralding a new era in targeted phototherapy., (Copyright © 2024. Published by Elsevier B.V.)

Vascular plant one-zinc finger (VOZ) transcription factors (TFs) play crucial roles in plant immunity. Nevertheless, how VOZs modulate defense signaling in response to elicitor-induced resistance is not fully understood. Here, the defense elicitor β-aminobutyric acid (BABA) resulted in the visible suppression of Rhizopus rot disease of peach fruit caused by Rhizopus stolonifer. Defense priming by BABA was notably associated with increased levels of salicylic acid (SA) and SA-dependent gene expression. Data-independent acquisition proteomic analysis revealed that two VOZ proteins (PpVOZ1 and PpVOZ2) were substantially upregulated in BABA-induced resistance (BABA-IR). Furthermore, the interaction of PpVOZ1 and PpVOZ2 and their potential target of the TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP)-family protein PpTCP2 screened from protein-protein interaction networks was confirmed by yeast two-hybrid (Y2H), luciferase complementation imaging and glutathione S-transferase pull-down assays. Furthermore, subcellular localization, yeast one-hybrid, electrophoretic mobility shift assay and dual-luciferase reporter assays demonstrated that nuclear localization of both PpVOZ1 and PpVOZ2 was critical for their contribution to BABA-IR, as these proteins potentiated the PpTCP2-mediated transcriptional activation of isochorismate synthase genes (ICS1/2). The overexpression of both PpVOZ1 and PpVOZ2 could activate the transcription of SA-dependent genes and provide disease resistance in transgenic Arabidopsis. In contrast, the ppvoz1 cas9 and ppvoz2 cas9 loss-of-function mutations and the voz1 cas9 voz2 cas9 double mutation attenuated BABA-IR against R. stolonifer. Therefore, the three identified positive TFs, PpVOZ1, PpVOZ2, and PpTCP2, synergistically contribute to the BABA-activated priming of systemic acquired resistance in postharvest peach fruit by a VOZ-TCP-ICS regulatory module., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

A better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in the islets of adult wild-type (WT) and diabetic mice. Our data show that more than ~30% of α/β-cells are innervated by sympathetic nerves in both WT and diabetic mice. Additionally, sympathetic innervated α/β-cells are reduced in diet-induced obese (DIO) mice, whereas sympathetic innervated β-cells are increased in db / db mice. In addition, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db / db mice but decreases glucose tolerance in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our understanding of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation.

The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH + CD133 + FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3'UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC., Competing Interests: Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics: This study was performed in line with the Ethics Committee of Shengjing Hospital of China Medical University. Animal care and experimental procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee at Shengjing Hospital of China Medical University (2022PS1036K and 2022PS1044K)., (© 2024. The Author(s).)

Proteomics provides an essential means of explaining the mechanisms underlying gene expression regulation. The proteomic mechanisms by which heavy metal hyperaccumulators respond to lead (Pb) stress remain largely unclear. To this end, we examined Pogonatherum crinitum (Thunb.) Kunth and employed proteomic sequencing technology to screen for differential proteins that respond to Pb stress. The connection between Pb-tolerant proteins in metabolic pathways and their functions were analyzed. Differences in the downstream molecules of Pb-resistant proteins in P. crinitum were also assessed. Furthermore, we utilized Parallel Reaction Monitoring (PRM) technology to validate the selected Pb-tolerant differential proteins across various stress concentration gradients. A total of 5275 protein families were identified, and 118 DEPs were observed between the stressed and control groups, including 76 upregulated and 42 downregulated proteins. Functional annotation analysis using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes revealed that Pb stress led to the upregulation of 16 proteins within P. crinitum leaves. These proteins were primarily involved in the metabolic processes of energy and carbohydrate metabolism (PcCht1, PcSPS5, PcGME-1, and PcPEP4) as well as protein translation and oxidative stress (PcHSP26.7, PcHSP18, PcCAT3, and PcCAT1). Bioinformatic analysis indicated that DEPs responding to Pb stress were primarily related to the MAPK signaling pathway, amino sugar and nucleotide sugar metabolism, and starch and sucrose metabolism. Pathway analysis revealed maltose, acetylcholine, N-acetylglucosamine, and oxalic acid as the downstream products. Moreover, the levels of these indicators all increased with increasing Pb concentrations. PRM of the 16 DEPs revealed that nine proteins were upregulated under different Pb concentrations. PRM and data-independent acquisition results for the upregulation of these nine DEPs were identical, suggesting the reliability of our analytical outcomes. In conclusion, the upregulation of specific proteins in P. crinitum enables the regulation of glucose metabolism and antioxidant balance within the plant and represents a mechanism underlying its Pb stress response., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shihong Guo reports equipment, drugs, or supplies, statistical analysis, and writing assistance were provided by Fujian Province Public Welfare Scientific Research Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

With the rapid progression of biotechnology, the significance translational research on glycolysis in molecular pharmacology has become increasingly evident. To deepen students' understanding of glycolytic processes and facilitate their comprehension of drug action mechanisms, we have developed a visual virtual simulation platform dedicated glycolysis. The educational approach commenced with theoretical lectures on glycolysis, followed by practical laboratory sessions where students measured glycolysis-related parameters such as hexokinase, pyruvate kinase, and lactate. Students then engaged with the virtual simulation training platform to explore glycolytic stress tests and positron emission tomography/computed tomography (PET/CT) imaging, with their progress tracked through an assessment mode. The study involved 67 s-year undergraduate students majoring in biomedical sciences, all of whom had received instruction in glucose metabolism theories and completed the associated questionnaires. The results showed that the students gained a deeper understanding of glycolysis and the clinical application of PET/CT imaging in the context of glycolysis. The majority also agreed that the integration of scientific and clinical cases in teaching is beneficial and that the project sparked their interest in scientific research. These findings align with existing literature that emphasizes the importance of innovative educational tools in enhancing student engagement and understanding of the underlying theories of the curriculum. This project designed an innovative glycolytic metabolism teaching system encompassing the monitoring of traditional glycolytic indicators, glycolytic stress tests, and PET/CT imaging based on glycolysis. The visual virtual simulation platform for glycolysis can serve as an innovative educational tool in the molecular pharmacology curriculum or other courses involving glycolysis, assisting students in deeply understanding the molecular mechanisms of glycolysis and its significance in disease and drug action., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Copper ion (Cu 2+ ), a crucial heavy metal ion, is closely associated with human health and the ecological environment. Imbalances in Cu 2+ can result in health issues for humans and damage to the ecosystem. Therefore, it is essential to detect Cu 2+ in the environment. However, current Cu 2+ sensors still face challenges such as limited detection range, poor detection limits, high costs, and complex preparation processes. Clearly, there is a need for a Cu 2+ sensor with an extensive detection range, low detection limit, cost-effectiveness, and simple preparation methods that enable online monitoring and real-time measurement of Cu 2+ ., Results: In this paper, a high-performance optical fiber fluorescent Cu 2+ sensor based on polyethylene glycol diacrylate (PEGDA) hydrogel encapsulated CdSe/ZnS quantum dots (QDs) is designed and fabricated. Due to the porous nature of PEGDA hydrogels, large-diameter CdSe/ZnS QDs are confined within the hydrogels, while small molecules Cu 2+ are allowed to permeate them. Cu 2+ reacts with QDs, resulting in the fluorescence quenching of QDs, which enables the detection of Cu 2+ . Experimental results show that the sensor can quantitatively analyze Cu 2+ in the concentration range of 0.1-200 μM, with a limit of detection (LOD) of only 0.8 nM, and the fastest response time is only 5 s. Additionally, the sensor exhibits strong specificity, has been successfully applied to real water sample detection, demonstrates good stability, and shows great potential for real-time Cu 2+ detection., Significance: The sensor possesses a large detection range and low LOD, and the synthesis of its core fluorescent probe is straightforward and expedient. Specifically, the fluorescent probe can be synthesized by subjecting a solution of hydrogel precursors doped with CdSe/ZnS QDs to UV irradiation for approximately 2 min. This method is particularly suitable for monitoring confined environments and holds significant implications for the production of Cu 2+ sensors capable of real-time detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increase in industrialization has led to a significant energy crisis, sparking interest in lignocellulosic biomass for fuel ethanol production because of its renewable characteristics. The complex composition of this biomass requires pretreatment to reduce inhibitors like furfural and hydroxymethylfurfural (HMF), which hinder enzymatic hydrolysis and fermentation, ultimately decreasing ethanol yields. This study investigates the detoxification mechanisms of furan aldehydes in Scheffersomyces stipitis, particularly through the upregulation of genes SsOYE2.2, SsOYE2.7, and SsOYE3.1 under furfural and HMF stress. Enzyme characterization determined that SsOye3.3p is the most active enzyme for reducing both compounds using NADPH. Notably, SsOye2.6p showed the highest catalytic efficiency towards furfural, while SsOye2.8p was optimal for HMF. The study also established the optimal temperature and pH for these enzymatic reactions. Importantly, SsOye2.5p displayed broad substrate specificity, indicating its potential in detoxifying various aldehydes in microbial cells. The findings suggest that genes linked to enhanced enzymatic properties were not significantly induced, indicating that S. stipitis has more substantial potential for furan aldehyde detoxification and can be developed as a chassis organism exhibiting furan aldehyde tolerance. These insights facilitate the development of novel enzymes to counter furan aldehyde inhibitors and the creation of furan aldehyde-tolerant strains via genetic engineering., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Esophageal squamous cell carcinoma (ESCC) is a malignant condition in humans. Anoikis-related genes (ARGs) are crucial to cancer progression. Therefore, more studies on the relationship between ARGs and ESCC are warranted., Methods: The study acquired ESCC-related transcriptome data from TCGA. Differentially expressed ARGs (DE-ARGs) were obtained by differential analysis and candidates were filtered out by survival analysis. Prognostic genes were determined by Cox and LASSO regression. A risk model was constructed based on prognostic gene expressions. An immune infiltration study was done to explain how these genes contribute to ESCC development. The IC50 test was adopted to assess the clinical response of chemotherapy drugs. Single cell analysis was performed on the GSE145370 dataset. Moreover, the prognostic gene expressions were detected by qRT-PCR., Results: 53 DE-ARGs were screened and four candidate genes including PBK, LAMC2, TNFSF10 and KL were obtained. Cox and LASSO regression identified the two prognostic genes, TNFSF10 and PBK. Immuno-infiltration analysis revealed positive associations of PBK with Macrophages M0 cells, and TNFSF10 with Macrophages M1 cells. The IC50 values of predicted drugs, in the case of Tozasertib 1096 and WIKI4 1940, were significantly variant between risk groups. Single cell analysis revealed that TNFSF10 and PBK levels were higher in epithelial cells than in other cells. The prognostic genes expression results by qRT-PCR were compatible with the dataset analysis., Conclusion: The study established an ARG prognosis model of ESCC. It provided a reference for the research of ARGs in ESCC.

Addressing the repair and regeneration of large bone defects poses significant challenges in bone tissue engineering. Despite the abundant evidence demonstrating the positive role of MSCs in osteogenesis, their limited osteogenic differentiation ability still needs to be improved. The present study used lipopolysaccharide (LPS) to enhance the osteogenic properties of ecto‑mesenchymal stem cells (EMSCs). Human nasal respiratory mucosa‑derived EMSCs were cultured on plates and stimulated with LPS for 5 days prior to undergoing osteogenic differentiation. The findings revealed that LPS effectively stimulated the osteogenic differentiation capacity of EMSCs, as evidenced by heightened alkaline phosphatase activity, elevated expression levels of osteogenic‑related proteins and enhanced mineralization of EMSCs. The present study also demonstrated that the augmentation occurred due to increased IL‑10 levels, although it was not solely attributable to this factor. Together, the findings illustrated that the LPS‑mediated adaptation of EMSCs is an active process driving osteogenic differentiation and could be a novel strategy for bone regeneration.

Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) is the predominant isoform of the catalytic subunit of PI3K in lymphocytes. Based on comprehensive bioinformatics, this study explores the functions of PIK3CD in diabetic kidney disease (DKD) progression in mice and B lymphocyte activity., Methods: Non-obese diabetic (NOD) mice that spontaneously develop DKD were applied as animal models. Lentiviral vector-mediated PIK3CD silencing was introduced in mice, followed by histological staining and biomarker assessments to evaluate DKD-associated symptoms. The activity of the Akt/mTOR signalling pathway was determined by western blot analysis. Following bioinformatics analyses, the interaction between POU class 2 homeobox 2 (POU2F2) and PIK3CD in B lymphocytes was determined by chromatin immunoprecipitation and luciferase reporter assays. Their functions in B cell function were identified by MTT, flow cytometry and IgG deposition assessment., Results: PIK3CD was found to be highly expressed in the kidney of DKD mice. Knockdown of PIK3CD inactivated the Akt/mTOR signalling, thus ameliorating tissue injury and fibrosis, enhancing the expression of AQP1 and decreasing urinary NGAL contents, UACR, BUN and β-NAG/creatinine ratio. These effects were negated by the Akt-specific activator SC79. POU2F2 was found to promote PIK3CD transcription by binding to its promoter, thus activating the Akt/mTOR pathway. Knockdown of POU2F2 suppressed B cell proliferation in vitro and decreased B cell population and IgG deposition in the mouse kidney. However, these trends were reversed upon additional PIK3CD overexpression., Conclusion: This study demonstrates that POU2F2 mediates PIK3CD-dependent Akt/mTOR signalling activation, thus enhancing B lymphocyte function and promoting DKD progression., (© 2024 Asian Pacific Society of Nephrology.)

Background and Objectives: Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI., Methods: Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed., Results: Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2-3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]., Discussion: Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) as a noninvasively measured index of right ventricular-pulmonary artery uncoupling is associated with poor outcomes in heart failure patients. However, the relationship by which the TAPSE/PASP is linked to atrial fibrillation (AF) in peritoneal dialysis (PD) patients is not clear. We aimed to investigate the relationship between the TAPSE/PASP and AF in PD patients., Methods: This study was divided into two parts. First, we included 329 PD patients. All the subjects provided detailed a medical history, laboratory analysis and transthoracic echocardiography on admission. We evaluated the differences in the TASPE/PASP ratios between the AF and non-AF groups. Second, a total of 121 patients were followed up to compare mortality between the AF and non-AF groups., Results: Age, BNP, RDW, LA, and septal E/e' were significantly higher, and TAPSE/PASP was significantly lower in patients with AF than in those without AF ( p  < 0.05). Moreover, the TAPSE/PASP was more pronounced in persistent AF patients. PD patients with AF had a greater risk of mortality (7.2%) than did those without AF (3.8%) after an average follow-up of 12 months. Kaplan-Meier analysis revealed that patients with TAPSE/PASP ratios ≤ 0.715 had a greater risk of mortality than did those with TAPSE/PASP ratios > 0.715., Conclusions: The results suggested that the TAPSE/PASP was lower in AF patients than in non-AF patients. The TAPSE/PASP may be a useful factor for predicting mortality in AF patients with PD, but large-scale prospective studies are needed for verification.

99m Tc is regarded as the most important medical isotope, and its supply issues have garnered significant attention. A simple and efficient separation method was performed for the production of 99m Tc from 100 Mo target in this study. The entire process involves accelerator irradiation, 99m Tc/ 100 Mo separation, and target material recovery. The key aspect is separation process, which including the high-temperature conversion of metal molybdenum targets and the selective solution of 99m Tc with normal saline. This method can separate highly pure 99m Tc within 1.5 h, with a separation efficiency exceeding 80%. The reagents used in the separation process are minimal, resulting in less radioactive waste. Additionally, the target material is easy to reclaim, with a recovery rate of over 95%., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, author-ship, and/or publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: For patients with advanced or unresectable hepatocellular carcinoma (HCC), safe and effective therapies are urgently needed to improve their long-term prognosis. Although the guidelines recommend first-line treatments such as sorafenib, lenvatinib, and atezolizumab in combination with bevacizumab (T+A) and second-line treatments such as regorafenib, the efficacy comparison between drugs is lacking, that is, a treatment is not recommended as the optimal or alternative choice for a specific patient population. Therefore, we will conduct a high-quality network meta-analysis based on Phase III randomized controlled trials (RCTs) to systematically evaluate and compare overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAE) of different treatment protocols in the context of first-line and second-line therapies, which are critical for clinical decision making and prognostic improvement in advanced HCC patients., Methods: The studies of interest were Phase III RCTs evaluating the efficacy or safety of first- or second-line therapies in patients with unresectable or advanced HCC. Literature published in English from the four databases of PubMed, Embase, Cochrane Library, and Web of Science was comprehensively searched from the inception to May 23, 2022. Outcomes of interest included OS, PFS, ORR, and SAE. A league table was developed to show the results of the comparison between different treatments. A histogram of cumulative probability was drawn to discuss the ranking probability of treatments based on different outcomes. The effectiveness and safety of various treatments were comprehensively considered and the two-dimensional diagram was plotted to guide clinical practice. The Gemtc package in R Studio was used for network meta-analysis in a Bayesian framework., Results: The results showed that HAIC-FO was superior to T+A regimen, regardless of OS, PFS or ORR. TACE combined with lenvatinib performed better than T+A in PFS, and ORR. In addition to the T+A regimen, Sintilimab combined with IBI305 and camrelizumab combined with apatinib were also associated with longer OS, PFS, and ORR, and their SAE incidence was not higher than that of T+A, especially for camrelizumab combined with apatinib, its safety was better than that of T+A regimen. There were no new treatments or combinations that were more effective than regorafenib. It was important to note that for PFS, the efficacy of apatinib and cabozantinib was not statistically different from that of regorafenib, so these two treatments could be used as alternative treatment options in cases where regorafenib was not tolerated or treatment failed., Conclusions: We conducted a network meta-analysis to evaluate the efficacy and safety of multiple treatment modalities by integrating the results of direct and indirect comparisons. This study included high-quality multicenter Phase III RCTs, collated and summarized all treatments involved in advanced or unresectable HCC in first-line and second-line settings, and compared with T+A and regorafenib, respectively, and ranked based on efficacy and safety to support clinical decision making., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous observational studies have suggested that thyroid function may be associated with functional outcome after ischemic stroke (IS). Nevertheless, the causal relationship remains unclear. This study aimed to explore the causal effect of thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (FT4), hyperthyroidism, and hypothyroidism] on functional outcome (based on the modified Rankin scale) after IS by two-sample Mendelian randomization (MR) analysis., Methods: Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, six additional MR methods (MR-Egger regression, weighted median, maximum likelihood, simple mode, weighted mode, and MR-PRESSO) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: (i) Cochrane's Q test for assessing heterogeneity; (ii) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; (iii) leave-one-out sensitivity test for determining stability., Results: The results of IVW indicated that elevated TSH levels significantly improved functional outcome after IS (OR = 0.74, 95 % CI: 0.57-0.97, P = 0.028). In addition, six additional MR methods suggested parallel results. However, no causal effect of FT4, hyperthyroidism, and hypothyroidism on functional outcome after IS was identified. In addition, sensitivity tests demonstrated the reliability of the MR analyses, suggesting that the MR analysis was not influenced by significant heterogeneity and horizontal pleiotropy., Conclusions: Our MR study supported that elevated TSH levels might improve functional outcome after IS. Therefore, regular monitoring and maintenance of stable TSH levels may benefit patients recovering from IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hydrogels are highly sought-after absorbent materials for absorbent pads; however, it is still challenging to achieve a satisfactory balance between mechanical performance, water absorption capacity, and active functionalities. In this work, we presented double-network hydrogels synthesized through acrylic acid (AA) polymerization in the presence of quaternized cellulose nanofibrils (QCNF) and Fe 3+ . Spectroscopic and microscopic analyses revealed that the combined QCNF and Fe 3+ facilitated the formation of double-network hydrogels with combined chemical and physical crosslinking. The synergistic effect of QCNF and Fe 3+ resulted in impressive mechanical properties, including tensile strength of 1.98 MPa, fracture elongation of 838.8 %, toughness of 7.47 MJ m -3 , and elastic modulus of 0.35 MPa. In comparison to the single-network PAA hydrogel, the PAA/QCNF/Fe 3+ (PQFe) hydrogels showed higher and relatively stable swelling ratios under varying pH levels and saline conditions. The PQFe hydrogels exhibited notable antioxidant activity, as evidenced by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, and demonstrated effective antibacterial activity against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). These hydrogels show promising potential as an absorbent interlayer in absorbent pads for active food packaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The abuse of amphetamine-type stimulants (ATSs) has caused irreversible harm to public safety and ecosystems. A novel polymerized deep eutectic solvent modified magnetic pomelo peel biochar (PMBC) was prepared, and the differences in adsorption of four abused amphetamine-type stimulants (ATSs: AMP, MAMP, MDA and MDMA) were due to varying hydrogen bonds quantities and strengths. PMBC showed excellent chemical reactivity to MDMA, with a maximum adsorption capacity of 926.13 μg g -1 , which was 3.25, 2.52 and 1.15 times higher than that of AMP, MAMP and MDA, respectively. Modern spectral analysis showed that there were a series of active centers (-COOH, -NH 2 and -OH) on the PMBC, which could form hydrogen bond networks with the nitrogen and oxygen functional groups of ATSs. In various chemical environments: pH level (4-11), inorganic ion and organic matter (humic acid), PMBC maintained high activity towards four ATSs. Additionally, the quantum chemical calculations revealed that the methylenedioxy bridge of ATSs can increase the active sites, and the -NH- and -NH 2 groups had different hydrogen bond formation capabilities, which together resulted in the adsorption order of PMBC on the four ATSs: MDMA > MDA > MAMP > AMP. Moreover, the hydrogen-bonding binding energies of several common hydrogen-bonding types were compared, including O-H····O, N-H····O/O-H····N and N-H···N. This study laid an empirical and theoretical foundation for the efficient capture of ATSs in water and contributed to the innovative design of materials., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shurui Cao reports financial support was provided by Chongqing Municipal Education Commission. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background & Aims: The pathophysiology of Crohn's-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses., Methods: Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry., Results: The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1 + monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells-inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments., Conclusions: CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate drivers' disengagement from nondriving related tasks (NDRT) during scheduled takeovers and to evaluate its impact on takeover performance., Background: During scheduled takeovers, drivers typically have sufficient time to prepare. However, inadequate disengagement from NDRTs can introduce safety risks., Method: Participants experienced scheduled takeovers using a driving simulator, undergoing two conditions, with and without an NDRT. We assessed their takeover performance and monitored their NDRT disengagement from visual, cognitive, and physical perspectives., Results: The study examined three NDRT disengagement timings (DTs): DT1 (disengaged before the takeover request), DT2 (disengaged after the request but before taking over), and DT3 (not disengaged). The impact of NDRT on takeover performance varied depending on DTs. Specifically, DT1 demonstrated no adverse effects; DT2 impaired takeover time, while DT3 impaired both takeover time and quality. Additionally, participants who displayed DT1 exhibited longer eye-off-NDRT duration and a higher eye-off-NDRT count during the prewarning stage compared to those with DT2 and DT3., Conclusion: Drivers can benefit from earlier disengagement from NDRTs, demonstrating resilience to the adverse effects of NDRTs on takeover performance. The disengagement of cognition is often delayed compared to that of eyes and hands, potentially leading to DT3. Moreover, visual disengagement from NDRTs during the prewarning stage could distinguish DT1 from the other two., Application: Our study emphasizes considering NDRT disengagement in designing systems for scheduled takeovers. Measures should be taken to promote early disengagement, facilitate cognitive disengagement, and employ visual disengagement during the prewarning period as predictive indicators of DTs.

Rationale and Objectives: This study aimed to propose a novel approach of lipiodol combined with drug-eluting beads transarterial chemoembolization (Lipiodol-DEB TACE) and to compare the safety and efficacy with DEB-TACE alone for patients with unresectable hepatocellular carcinoma (HCC)., Materials and Methods: From the database of four centers, the records of patients with HCC who received DEB-TACE or Lipiodol-DEB TACE as initial treatment were retrospectively evaluated. The tumor response was measured based on the Modified Response Evaluation Criteria in Solid Tumors. Overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared between two groups., Results: A total of 244 patients were included with 160 patients receiving DEB-TACE and 84 patients receiving Lipiodol-DEB TACE. Lipiodol-DEB TACE group had higher objective response rate (86.9 % vs. 76.3 %), higher disease control rate (97.6 % vs. 88.8 %), longer median OS (42.6 vs. 25.8 months) and longer median PFS (34.0 vs. 17.0 months) than DEB-TACE group (P < 0.05). There was no significant difference observed in the incidence of AEs between two groups. Cox analysis identified total bilirubin level, maximum tumor diameter, TACE method and portal vein invasion as independent prognostic factors., Conclusion: Lipiodol-DEB TACE was a safe option and associated with improved tumor response and survival outcome compared to DEB-TACE alone for selected patients with HCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Background: Melatonin, a hormone present in animals and some plants, has garnered attention for its potential in preserving harvested produce. Softening due to changes in cell wall composition and wilting caused by weight loss are the major reasons for the loss of commercial value in postharvest okra. This study aimed to evaluate the impact of melatonin on the softening and weight loss of postharvest okra., Results: The results revealed that the application of melatonin had a significant influence on the maintenance of fruit firmness by inhibiting the breakdown and dissolution of cell wall polysaccharides by suppressing the expression of specific genes responsible for cell wall degradation in okra. Conversely, melatonin treatment positively influenced the expression of genes involved in the synthesis of cell wall components. Furthermore, the treatment exhibited notable benefits in reducing weight loss in okra, which was accomplished by promoting the closure of stomata - the tiny pores on the surface of the fruit., Conclusion: Melatonin could serve as a novel approach to reduce water loss, delay fruit softening and extend the shelf life of okra. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Green pepper quality often deteriorates during storage because of membrane lipid damage and oxidative stress. This study investigated the effects of exogenous melatonin (MT) on green pepper storage quality, membrane lipids, and antioxidant metabolism. The results showed that MT increased the activities of superoxide dismutase, catalase, ascorbate peroxidase, peroxidase, monodehydroascorbate reductase, and dehydroascorbate reductase in green peppers compared to the control group. It upregulated expression of multiple enzymes; reduced accumulation of reactive oxygen species such as dehydroascorbic acid, H 2 O 2 , and O 2 .- ; and maintained high ascorbic acid, glutathione, coenzyme II, and nicotinamide adenine dinucleotide while reducing oxidized glutathione levels. In addition, MT decreased lipoxygenase and phospholipase D activities, downregulated ReLOX and RePLD expression, and delayed the degradation of phosphatidylcholine, phosphatidylethanolamine, and oleic, linoleic, and linolenic acids in green peppers. These results suggest that MT helps to improve the chilling injury and quality of green peppers and extends shelf life., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Context: Four algorithms with relatively balanced complexity and accuracy in deep learning classification algorithm were selected for differential diagnosis of primary membranous nephropathy (PMN)., Objective: This study explored the most suitable classification algorithm for PMN identification, and to provide data reference for PMN diagnosis research., Methods: A total of 500 patients were referred to Luo-he Central Hospital from 2019 to 2021. All patients were diagnosed with primary glomerular disease confirmed by renal biopsy, contained 322 cases of PMN, the 178 cases of non-PMN. Using the decision tree, random forest, support vector machine, and extreme gradient boosting (Xgboost) to establish a differential diagnosis model for PMN and non-PMN. Based on the true positive rate, true negative rate, false-positive rate, false-negative rate, accuracy, feature work area under the curve (AUC) of subjects, the best performance of the model was chosen., Results: The efficiency of the Xgboost model based on the above evaluation indicators was the highest, which the diagnosis of PMN of the sensitivity and specificity, respectively 92% and 96%., Conclusions: The differential diagnosis model for PMN was established successfully and the efficiency performance of the Xgboost model was the best. It could be used for the clinical diagnosis of PMN.

Recurrent laryngeal nerve (RLN) injury during neck surgery can cause significant morbidity related to vocal cord (VC) dysfunction. VC electromyography (EMG) is used to aid in the identification of the RLN and can reduce the probability of inadvertent surgical injury. Errors in the placement of specialized EMG endotracheal tubes (ETT) can result in unreliable signals, false-negative responses, or no response when stimulating the RLN. We describe a novel educational protocol developed to optimize uniformity in the placement of ETTs to improve the reliability of RLN monitoring. An intraoperative neuromonitoring database was queried for all neck surgeries requiring RLN monitoring. Data points extracted for all cases requiring EMG monitoring for neck procedures. Free running and stimulated EMG were monitored and continuously recorded by a certified technologist. Alerts were compared between 2013-14 and 2015-18 using a two-sample test of proportions. Significant reductions in alerts were demonstrated after protocol implementation (7.5% pre-implementation to 2.1% post). Alerts were compared between 2013-14 (overall alert rate of 1.8%, pre-implementation period) and 2015-18 (overall alert rate of 2.8%, post-implementation period). Protocolization for placement of EMG-ETT improved accuracy in EMG monitoring. In the follow-up cohort of 1,080 patients, use of this protocol continued to reduce the rate of alerts related to ETT malposition, confirming the sustainability of this intervention through routine education. The risk of nerve injury is reduced when the rate of alerts is minimized. Scheduled or continuous protocol education of anesthesia personnel should continue to ensure compliance with protocol.

Objective: This study was designed to evaluate the safety and efficacy of injections of concentrated growth factors (CGF) for hair growth promotion in androgenetic alopecia (AGA) patients., Methods: A retrospective review of AGA patients treated with injections of CGF at our center from October 2021 to April 2023 was performed. A total of 3 injections were administered every 3-4 weeks apart, and evaluation were performed before the first injection and at 3 months, 6 months later. The outcomes were assessed by trichoscopy photomicrographs and the Global Aesthetic Improvement Scale (GAIS)., Results: At 3 months after the first injection, the hair density and hair growth ratio were significantly improved. Significant improvements were found in GAIS score by both patients and independent doctors and the hair growth promotion was sustained for 6 months after first treatment., Conclusions: According to this tiny single-arm trial, the use of CGF injection may help AGA by increasing terminal hair density and hair density. No severe topical or systemic adverse events occurred during the treatment., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fine motor control difficulties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was significantly downregulated in the medial prefrontal cortex of young mice after multiple sevoflurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identified as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway., Competing Interests: Conflict of interest: All authors claim that there are no potential conflicts of interest for the research, authorship, and publication of this article., (© 2024. The Author(s).)

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC 50 = 0.7 μM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

For penetrating and deep non-compressible bleeding, hemostatic materials need to meet the demand of easy filling and rapid expansion to close the wound. However, developing an expandable material with sufficient mechanical strength remains a challenge. This study proposed an improved non-solvent induced phase separation (NIPS) method to prepare polyvinyl alcohol/chitosan (PVA/CS) cryogel with large pore structure (70-75 um) and enhanced mechanical properties. The pore structure on the surface enables blood to quickly enter the dry and shape-fixed PVA/CS cryogel, triggering volume expansion. By regulating the hydrogen bond of PVA molecules by CS, the hydrophilia of cryogel was enhanced and the full volume recovery time of PVA/CS 15% was shortened (27 ± 3 s). The aggregation of PVA molecular in solution enhances the crosslinking, endowing the prepared PVA/CS cryogel with good mechanical properties. The tensile strength of PVA/CS cryogel is up to 0.694 ± 0.044 MPa, and the compressive strength reach to 0.32 ± 0.04 MPa with 75 % compression. The good mechanical properties are beneficial for providing physical support. The preparation method does not require the introduction of toxic chemical cross-linking agents and complicated operation process, which has potential applications in non-compressible hemostasis., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest., (Published by Elsevier B.V.)

KMT2D, a H3K4me1 methyltransferase primarily regulating enhancers, is a leading cause of KABUKI syndrome. This multisystem disorder leads to craniofacial and cognitive abnormalities, possibly through neural crest and neuronal lineages. However, the impacted cell-of-origin and molecular mechanism of KMT2D during the development of KABUKI disease remains unknown. Here we have optimized a brain organoid model to investigate neural crest and neuronal differentiation. To pinpoint KMT2D's enhancer target, we developed a genome-wide cis-regulatory element explorer (GREE) based on single-cell multiomic integration. Single cell RNA-seq revealed that KMT2D-knockout (KO) and patient-derived organoids exhibited neural crest deformities and GABAergic overproduction. Mechanistically, GREE identified that KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer, providing the microenvironment for neural crest and neuronal development. Interestingly, KMT2D-mutated mice displayed decreased WNT3A expression in the diencephalon roof plate, indicating impaired niche cell function. Deleting the WNT3A enhancer in the organoids presented phenotypic similarities to KMT2D-depletion, emphasizing the WNT3A enhancer as the predominant target of KMT2D. Conversely, reactivating WNT signaling in KMT2D-KO rescued the lineage defects by restoring the microenvironment. Overall, our discovery of KMT2D's primary target provides insights for reconciling complex phenotypes of KABUKI syndrome and establishes a new paradigm for dissecting the mechanisms of genetic disorders from genotype to phenotype., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The effects of γ-aminobutyric (GABA) on enzymatic browning, storage quality, membrane and reactive oxygen species (ROS) metabolism in fresh-cut stem lettuce were investigated. The results illustrated that GABA treatment delayed browning degree, polyphenol oxidase (PPO) activity and the expression of LsPPO. Meanwhile, higher chlorophyll and ascorbic acid contents were exhibited in GABA-treated stem lettuce, as well as the slower microbial propagation. Further investigation revealed that exogenous GABA application declined malondialdehyde content, electrolyte leakage and the enzyme activities of membrane metabolism, and the expression levels of related genes were also downregulated. In addition, GABA treatment scavenged ROS and strengthened the enzyme activities of ROS metabolism, as well as the expression levels of corresponding genes. Taken together, these findings implied that the repressed enzymatic browning and microbial propagation in GABA-treated stem lettuce were due to the inhibition of ROS accumulation, enhancement of membrane stability and increased resistance to oxidation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)