Uptake and Biotransformation of Guvermectin in Three Crops after In Vivo and In Vitro Exposure.

Guvermectin, as a novel nucleoside-like biopesticide, could increase the rice yield excellently, but the potential environmental behaviors remain unclear, which pose potential health risks. Therefore, the uptake and biotransformation of guvermectin in three types of crops (rice, lettuce, and carrot) were first evaluated with a hydroponic system. Guvermectin could be rapidly absorbed and reached equilibrium in roots (12-36 h) and shoots (24-60 h) in three plants, and guvermectin was also vulnerable to dissipation in roots (t1/2 1.02-3.65 h) and shoots (t1/2 9.30-17.91 h). In addition, 8 phase I and 2 phase II metabolites, transformed from guvermectin degradation in vivo and in vitro exposure, were identified, and one was confirmed as psicofuranine, which had antibacterial and antitumor properties; other metabolites were nucleoside-like chemicals. Molecular simulation and quantitative polymerase chain reaction further demonstrated that guvermectin was metabolized by the catabolism pathway of an endogenous nucleotide. Guvermectin had similar metabolites in three plants, but the biotransformation ability had a strong species dependence. In addition, all the metabolites exhibit neglectable toxicities (bioconcentration factor <2000 L/kg b.w., LC50,rat > 5000 mg/kg b.w.) by prediction. The study provided valuable evidence for the application of guvermectin and a better understanding of the biological behavior of nucleoside-like pesticides.

Customizable Click Biochemistry Strategy for the Design and Preparation of Glucagon-like Peptide-1 Conjugates and Coagonists.

The development of oligomeric glucagon-like peptide-1 (GLP-1) and GLP-1-containing coagonists holds promise for enhancing the therapeutic potential of the GLP-1-based drugs for treating type 2 diabetes mellitus (T2DM). Here, we report a facile, efficient, and customizable strategy based on genetically encoded SpyCatcher-SpyTag chemistry and an inducible, cleavable self-aggregating tag (icSAT) scheme. icSAT-tagged SpyTag-fused GLP-1 and the dimeric or trimeric SpyCatcher scaffold were designed for dimeric or trimeric GLP-1, while icSAT-tagged SpyCatcher-fused GLP-1 and the icSAT-tagged SpyTag-fused GIP were designed for dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. These SpyCatcher- and SpyTag-fused protein pairs were spontaneously ligated directly from the cell lysates. The subsequent icSAT scheme, coupled with a two-step standard column purification, resulted in target proteins with authentic N-termini, with yields ranging from 35 to 65 mg/L and purities exceeding 99%. In vitro assays revealed 3.0- to 4.1-fold increased activities for dimeric and trimeric GLP-1 compared to mono-GLP-1. The dual GLP-1/GIP receptor agonist exhibited balanced activity toward the GLP-1 receptor or the GIP receptor. All the proteins exhibited 1.8- to 3.0-fold prolonged half-lives in human serum compared to mono-GLP-1 or GIP. This study provides a generally applicable click biochemistry strategy for developing oligomeric or dual peptide/protein-based drug candidates.

Deciphering the therapeutic potential of SheXiangXinTongNing: Interplay between gut microbiota and brain metabolomics in a CUMS mice model, with a focus on tryptophan metabolism.

Depression, a prevalent and multifaceted mental disorder, has emerged as a significant public health concern due to its escalating prevalence and heightened risk of severe suicidality. Given its profound impact, the imperative for preventing and intervening in depression is paramount. Substantial evidence underscores intricate connections between depression and cardiovascular health. SheXiangXinTongNing (XTN), a recognized traditional Chinese medicine for treating Coronary Heart Disease (CHD), prompted our exploration into its antidepressant effects and underlying mechanisms. In this investigation, we assessed XTN's antidepressant potential using the chronic unpredictable mild stress (CUMS) mice model and behavioral tests. Employing network pharmacology, we delved into the intricate mechanisms at play. We characterized the microbial composition and function in CUMS mice, both with and without XTN treatment, utilizing 16S rRNA sequencing and metabolomics analysis. The joint analysis of these results via Cytoscape identified pivotal metabolic pathways. In the realm of network pharmacology, XTN administration exhibited antidepressant effects by modulating pathways such as IL-17, neuroactive ligand-receptor interaction, PI3K-Akt, cAMP, calcium, and dopamine synapse signaling pathways. Our findings revealed that XTN significantly mitigated depression-like symptoms and cognitive deficits in CUMS mice by inhibiting neuroinflammation and pyroptosis. Furthermore, 16S rRNA sequencing unveiled that XTN increased the alpha-diversity and beta-diversity of the gut microbiome in CUMS mice. Metabolomics analysis identified brain metabolites crucial for distinguishing between the CUMS and CUMS+XTN groups, with a focus on pathways like Tryptophan metabolism and Linoleic acid metabolism. Notably, specific bacterial families, including Alloprevotella, Helicobacter, Allobaculum, and Clostridia, exhibited robust co-occurring relationships with brain tryptophan metabolomics, hinting at the potential mediating role of gut microbiome alterations and metabolites in the efficacy of XTN treatment. In conclusion, our study unveils modifications in microbial compositions and metabolic functions may be pivotal in understanding the response to XTN treatment, offering novel insights into the mechanisms underpinning the efficacy of antidepressants.

Advanced solid-state NMR spectroscopy and its applications in zeolite chemistry.

Solid-state NMR spectroscopy (ssNMR) can provide details about the structure, host-guest/guest-guest interactions and dynamic behavior of materials at atomic length scales. A crucial use of ssNMR is for the characterization of zeolite catalysts that are extensively employed in industrial catalytic processes. This review aims to spotlight the recent advancements in ssNMR spectroscopy and its application to zeolite chemistry. We first review the current ssNMR methods and techniques that are relevant to characterize zeolite catalysts, including advanced multinuclear and multidimensional experiments, in situ NMR techniques and hyperpolarization methods. Of these, the methodology development on half-integer quadrupolar nuclei is emphasized, which represent about two-thirds of stable NMR-active nuclei and are widely present in catalytic materials. Subsequently, we introduce the recent progress in understanding zeolite chemistry with the aid of these ssNMR methods and techniques, with a specific focus on the investigation of zeolite framework structures, zeolite crystallization mechanisms, surface active/acidic sites, host-guest/guest-guest interactions, and catalytic reaction mechanisms.

Magnetic beads and GO-assisted enzyme-free signal amplification fluorescent biosensors for disease diagnosis.

Cancer detection is still a major challenge in public health. Identification of oncogene is the first step toward solving this problem. Studies have revealed that various cancers are associated with miRNA expression. Therefore, the sensitive detection of miRNA is substantially important to solve the cancer problem. In this study, let-7a, a representative substance of miRNA, was selected as the detection target. With the assistance of magnetic beads commonly used in biosensors and self-synthesized graphene oxide materials, specificity and sensitivity detection of the target gene let-7a were achieved via protease-free signal amplification. The limit of detection (LOD) was as low as 15.015pM. The fluorescence signal intensity showed a good linear relationship with the logarithm of let-7a concentration. The biosensor could also detect let-7a in complex human serum samples. Overall, this fluorescent biosensor is not only simple to operate, but also strongly specificity to detect let-7a. Therefore, it has substantial potential for application in the early diagnosis of clinical medicine and biological research.

Ketogenesis attenuated KLF5 disrupts iron homeostasis via LIF to confer oxaliplatin vulnerability in colorectal cancer.

Oxaliplatin has been included as a basal drug in various chemotherapy regimens for colorectal cancer (CRC), a global health concern. However, acquired resistance to oxaliplatin affects the prognosis. This study aimed to determine whether the consumption of a KD increases the sensitivity of CRC cells to oxaliplatin via the inhibition of a classical stem cell marker, Krupple-like factor 5 (KLF5). KLF5 functions as a transcription factor for the leukemia inhibitory factor (LIF) and directly binds to its promoter region. LIF upregulation induces dephosphorylation of metal regulatory transcription factor 1 (MTF1), which is recruited to the promoter area of Ferroportin (FPN1), the only cellular iron exporter. FPN1 upregulation reduces the labile iron pool (LIP) and ferroptosis in CRC cells. KLF5 knockdown inhibits the LIF/MTF1/FPN1 axis and induces iron overload, thereby conferring sensitivity to oxaliplatin to CRC cells. KD mimicked KLF5 silencing and sensitized CRC cells to oxaliplatin via a similar mechanism. Thus, potential correlations were observed among ketogenesis, stemness, and iron homeostasis. This finding can be used to formulate a new strategy for overcoming oxaliplatin resistance in patients with CRC.

Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.

Risk factors and management of gastrointestinal bleeding in patients with or without antiplatelet and anticoagulation therapy: a multicenter real-world prospective study.

BACKGROUND: Antiplatelet and anticoagulation drugs complicate acute gastrointestinal bleeding (GIB) patients. Limited data about the risk factors and patient management has been presented. This study explored the association between previous antiplatelet or anticoagulant drug usage and clinical outcomes in GIB patients to improve awareness further and optimize treatment. METHODS: We conducted a multicenter, non-interventional, real-world prospective study in 106 hospitals in 23 provinces in China. GIB patients confirmed in the emergency department were included and were grouped according to previous drug histories. Univariate analysis, multivariate logistic regression, and multivariate stratification models were performed separately to investigate the associations. RESULTS: A total of 2299 patients (57.23 ± 17.21 years old, 68.3% male) were included, of whom 20.1% and 2.9% received antiplatelet and anticoagulation therapy, respectively. The all-cause 28-day mortality rates in patients without antiplatelet or anticoagulants, patients undergoing antiplatelet treatment, and patients with anticoagulation therapy were 2.8%, 4.6%, and 10.5%, respectively. After adjusting for confounding factors, both antiplatelet [odd ratio (OR), 2.92; 95% confidence interval (CI), 1.48-5.76; p = 0.002] and anticoagulation therapy (OR, 8.87; 95% CI, 3.02-26.02; p < 0.001) were associated with higher 28-day mortality. In the subgroup analysis, blood transfusion, especially red blood cell transfusion, in patients undergoing antiplatelet and anticoagulation therapy was associated with a decreased death risk. CONCLUSION: We confirmed an association between concurrent antiplatelet or anticoagulation therapy in GIB patients and elevated 28-day mortality. Blood transfusions could improve poor outcomes in such patients.

A comprehensive AI model development framework for consistent Gleason grading.

BACKGROUND: Artificial Intelligence(AI)-based solutions for Gleason grading hold promise for pathologists, while image quality inconsistency, continuous data integration needs, and limited generalizability hinder their adoption and scalability. METHODS: We present a comprehensive digital pathology workflow for AI-assisted Gleason grading. It incorporates A!MagQC (image quality control), A!HistoClouds (cloud-based annotation), Pathologist-AI Interaction (PAI) for continuous model improvement, Trained on Akoya-scanned images only, the model utilizes color augmentation and image appearance migration to address scanner variations. We evaluate it on Whole Slide Images (WSI) from another five scanners and conduct validations with pathologists to assess AI efficacy and PAI. RESULTS: Our model achieves an average F1 score of 0.80 on annotations and 0.71 Quadratic Weighted Kappa on WSIs for Akoya-scanned images. Applying our generalization solution increases the average F1 score for Gleason pattern detection from 0.73 to 0.88 on images from other scanners. The model accelerates Gleason scoring time by 43% while maintaining accuracy. Additionally, PAI improve annotation efficiency by 2.5 times and led to further improvements in model performance. CONCLUSIONS: This pipeline represents a notable advancement in AI-assisted Gleason grading for improved consistency, accuracy, and efficiency. Unlike previous methods limited by scanner specificity, our model achieves outstanding performance across diverse scanners. This improvement paves the way for its seamless integration into clinical workflows.

Gleason grading is a well-accepted diagnostic standard to assess the severity of prostate cancer in patients' tissue samples, based on how abnormal the cells in their prostate tumor look under a microscope. This process can be complex and time-consuming. We explore how artificial intelligence (AI) can help pathologists perform Gleason grading more efficiently and consistently. We build an AI-based system which automatically checks image quality, standardizes the appearance of images from different equipment, learns from pathologists' feedback, and constantly improves model performance. Testing shows that our approach achieves consistent results across different equipment and improves efficiency of the grading process. With further testing and implementation in the clinic, our approach could potentially improve prostate cancer diagnosis and management.

Characteristics of Dialdehyde Cellulose Nanofibrils Derived from Cotton Linter Fibers and Wood Fibers.

Two types of cellulose nanofibrils (CNFs) were isolated from cotton linter fibers and hardwood fibers through mechanical fibrillation methods. The dialdehyde cellulose nanofibrils (DACNFs) were prepared through the periodate oxidation method, and their morphological and structural properties were investigated. The characteristics of the DACNFs during the concentration process were also explored. The AFM analysis results showed that the mean diameters of wood fiber-based CNFs and cotton fiber-based CNFs were about 52.03 nm and 69.51 nm, respectively. However, the periodate oxidation treatment process obviously reduced the nanofibril size and destroyed the crystalline region of the nanofibrils. Due to the high crystallinity of cotton fibers, the cotton fiber-based DACNFs exhibited a lower aldehyde content and suspension stability compared to the wood fiber-based DACNFs. For the concentration process of the DACNF suspension, the bound water content of the concentrated cotton fiber-based DACNFs was lowered to 0.41 g/g, which indicated that the cotton fiber-based DACNFs could have good redispersibility. Both the wood fiber-based and cotton fiber-based DACNF films showed relatively good transmittance and mechanical strength. In addition, to the cotton fiber-based DACNF films had a very low swelling ratio, and the barrier water vapor and oxygen properties of the redispersed cotton fiber-based DACNF films decreased by very little. In sum, this study has demonstrated that cotton fibers could serve as an effective alternative to wood fibers for preparing CNFs, and that cotton fiber-based DACNFs have huge application prospects in the field of packaging film materials due to their stable properties during the concentration process.

Combined OLA1 and CLEC3B Gene Is a Prognostic Signature for Hepatocellular Carcinoma and Impact Tumor Progression.

Hepatocellular carcinoma (HCC), partly because of its complexity and high heterogeneity, has a poor prognosis and an extremely high mortality rate. In this study, mRNA sequencing expression profiles and relevant clinical data of HCC patients were gathered from different public databases. Kaplan-Meier survival curves as well as ROC curves validated that OLA1|CLEC3B was an independent predictor with better predictive capability of HCC prognosis compared to OLA1 and CLEC3B separately. Further, the cell transfection experiment verified that knockdown of OLA1 inhibited cell proliferation, facilitated apoptosis, and improved sensitivity of HCC cells to gemcitabine. In this study, the prognostic model of HCC composed of OLA1/CLEC3B genes was constructed and verified, and the prediction ability was favorable. A higher level of OLA1 along with a lower level of CEC3B is a sign of poor prognosis in HCC. We revealed a novel gene pair OLA1|CLEC3B overexpressed in HCC patients, which may serve as a promising independent predictor of HCC survival and an approach for innovative diagnostic and therapeutic strategies.

Nd:YAG water mist laser treatment for giant gestational gingival tumor: A case report.

BACKGROUND: This case of gestational gingival tumor is huge and extremely rare in clinical practice. As the growth location of this gingival tumor is in the upper anterior tooth area, it seriously affects the pregnant woman's speech and food, causing great pain to the patient. The use of Nd:YGA water mist laser to remove the gingival tumor resulted in minimal intraoperative bleeding, minimal adverse reactions, and good postoperative healing, which is worthy of clinical promotion and application. CASE SUMMARY: The patient, a pregnant woman, reported a large lump in her mouth on the first day of postpartum treatment. Based on medical history and clinical examination, the diagnosis was diagnosed as gestational gingival tumor. Postoperative pathological biopsy also confirmed this diagnosis. The use of Nd:YAG water mist laser to remove the tumor resulted in minimal intraoperative bleeding, clear surgical field of view, short surgical time, and good postoperative healing. CONCLUSION: In comparison to traditional surgery, Nd:YAG water mist laser surgery is minimally invasive, minimizes cell damage, reduces bleeding, ensures a clear field of vision, and virtually eliminates postoperative edema, carbonization, and the risk of cross infection. It has unique advantages in oral soft tissue surgery for pregnant patients. Therefore, the clinical application of Nd:YAG water mist laser for the treatment of gestational gingival tumors is an ideal choice.

dMXP: A De Novo Small-Molecule 3D Structure Predictor with Graph Attention Networks.

Generating the three-dimensional (3D) structure of small molecules is crucial in both structure- and ligand-based drug design. Structure-based drug design needs bioactive conformations of compounds for lead identification and optimization. Ligand-based drug design techniques, such as 3D shape similarity search, 3D pharmacophore model, 3D-QSAR, etc., all require high-quality small-molecule ligand conformations to obtain reliable results. Although predicting a small molecular bioactive conformer requires information from the receptor, a crystal structure of the molecule is a proper approximation to its bioactive conformer in a specific receptor because the binding pose of a small molecule in its receptor's binding pockets should be energetically close to the crystal structures. This study presents a de novo small molecular structure predictor (dMXP) with graph attention networks based on crystal data derived from the Cambridge Structural Database (CSD) combined with molecular electrostatic information calculated by density-functional theory (DFT). Two featuring strategies (topological and atomic partial change features) were employed to explore the relation between these features and the 3D crystal structure of a small molecule. These features were then assembled to construct the holistic 3D crystal structure of a molecule. Molecular graphs were encoded using a graph attention mechanism to deal with the issues of the inconsistencies of local substructures contributing to the entire molecular structure. The root-mean-square deviation (RMSDs) of approximately 80% dMXP predicted structures and the native binding poses within receptors are less than 2.0 Å.

Water-soluble silver nanoclusters with multicolor fluorescence generated by dialdehyde nanofibrillated cellulose for biological imaging.

Water-soluble silver nanoclusters (AgNCs) as a new type of fluorescent material have attracted much attention for their remarkable optical properties and excellent cytocompatibility. However, it is still challenging to synthesize water-soluble AgNCs with good cytocompatibility and excellent fluorescence. Herein, the dialdehyde nanofibrillated cellulose (DANFC)- reduced water-soluble AgNCs capped by glutathione (GSH) with tunable fluorescence emissions were first reported. The DANFC provides a mild reduction environment and crystal growth system for the coordination between silver ions and GSH compared to conventional methods using strong reducing agents. The AgNCs with intense red fluorescence (R-AgNCs@GSH, size ∼2.24 nm) and green fluorescence (G-AgNCs@GSH, size ∼1.93 nm) were produced by varying the ratios of silver sources and ligands, and could maintain stable fluorescence intensity over 6 months. Moreover, the CCK-8 study demonstrated that the R-AgNCs@GSH and G-AgNCs@GSH reduced by DANFC of excellent cytocompatibility (cell viability >90 %) and enable precise multicolor intracellular imaging of Hela cells in 1 h. This work proposes a novel method to synthesize water-soluble AgNCs with tunable fluorescence emission at room temperature based on the classical silver- mirror reaction (SMR) using DANFC as reducing agent, and the synthesized fluorescent AgNCs have great potential as novel luminescent nanomaterials in biological research.

The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia.

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

18F-FDG PET/CT of Intracholecystic Papillary Neoplasm in Cystic Neck and Duct.

ABSTRACT: We report 18F-FDG PET/CT appearances of intracholecystic papillary neoplasm (ICPN) in the gallbladder neck and duct of a 74-year-old woman with a history of hepatitis B cirrhosis. The lesion presented with a large and sessile soft mass in the neck and duct of gallbladder with obvious glucose metabolism on PET/CT images, which was confirmed pathologically as ICPN (gastric foveolar type) with high-grade intraepithelial neoplasia. ICPN localized in the gallbladder neck and duct is extremely rare, and is easily misdiagnosed as gallbladder carcinoma. Our report aids in the application of PET/CT in the differential diagnosis of ICPN and guiding early surgery.

Tunable and mode-locked Tm,Ho:GdScO3 laser.

A novel, to the best of our knowledge, Tm,Ho:GdScO3 crystal grown using the Czochralski method was investigated for its polarized spectroscopic properties and laser performance in both tunable continuous-wave (CW) and mode-locked regimes. The crystal's multisite structure (Gd3+/Sc3+ site) and Tm3+/Ho3+ dopants contributed to spectral broadening, enabling a tunable laser operation from 1914 to 2125 nm (with a broad range of 215 nm). Additionally, a pulse duration of 72 fs was achieved for E || b polarization. These results demonstrate the potential of the Tm,Ho:GdScO3 perovskite crystal as a promising gain material for ultrafast lasers operating around 2 µm.

In Situ Monitoring and Tuning Multilayer Stacking of Polymer Lamellar Crystals in Solution with Aggregation-Induced Emission.

Many types of self-assembled 2D materials with fascinating morphologies and novel properties have been prepared and used in solution. However, it is still a challenge to monitor their in situ growth in solution and to control the number of layers in these materials. Here, we demonstrate that the aggregation-induced emission (AIE) effect can be applied for the in situ decoupled tracing of the lateral growth and multilayer stacking of polymer lamellar crystals in solution. Multilayer stacking considerably enhances the photoluminescence intensity of the AIE molecules sandwiched between two layers of lamellar crystals, which is 2.4 times that on the surface of monolayer crystals. Both variation of the self-seeding temperature of crystal seeds and addition of a trace amount of long polymer chains during growth can control multilayer lamellar stacking, which are applied to produce tunable fluorescent patterns for functional applications.