Explainable Fault Diagnosis Using Invertible Neural Networks-Part I: A Left Manifold-Based Solution.

The series includes two parts, articulating the two novel avenues of research on intelligent fault diagnosis (FD) for nonlinear feedback control systems. In Part I of the series, we design a novel FD paradigm by elaborating an invertible neural network (INN) for feedback control systems. With the aid of a left manifold, the core idea behind the INN-based FD scheme is as follows: 1) formulation of residual generator used for FD as a projection of system data onto the null space that has the same dimension as system outputs; 2) in a topological space, elaboration of a homeomorphism that delivers an invertible relationship between system outputs and residual signals when the system input is given; and 3) skillful introduction of both the master and slave objective functions to achieve system/parameter identification with information loseless property. Comparing with the existing FD approaches, the three superior strengths of the proposed FD scheme deserving mentation are as follows: 1) it specializes in nonlinear feedback control systems; 2) it can effectively avoid the overfitting problem when approximating or learning nonlinear system dynamics; and 3) control theory guides the whole design, ensuring the interpretability of the learning process. Finally, two studies on nonlinear systems demonstrate the feasibility of the invertible left manifold (ILM)-based FD strategy. Part I would contribute to the future development of machine learning (ML)-based system identification and explainable FD approaches, and also benefits the right manifold-based FD designs in Part II.

A Minimalist Method for Fully Oxygen-Tolerant RAFT Polymerization through Sulfur-Centered Trithiocarbonate Radical Initiation.

In recent years, the fully oxygen-tolerant reversible deactivation radical polymerization (RDRP) has become a highly researched area. In this contribution, a new and minimalist method is successfully employed to accomplish fully oxygen-tolerant reversible addition-fragmentation chain transfer (RAFT) polymerization using bis(trithiocarbonate) disulfides (BisTTC) as an iniferter agent, where the released sulfur-centered trithiocarbonate (TTC) radical can initiate monomer. Furthermore, polymerization kinetics revealed the typical "living" features of this polymerization system. More importantly, by high-throughput screening, it is found that dodecyl-substituted TTC is responsible for the fully oxygen-tolerant RAFT polymerization though trithiocarbonate radical initiation and R radical deoxygenation. It is believed that trithiocarbonate radical initiation strategy provides a powerful and minimalist tool for fully oxygen-tolerant RDRPs.

Comprehensive applications of the artificial intelligence technology in new drug research and development.

Purpose: Target-based strategy is a prevalent means of drug research and development (R&D), since targets provide effector molecules of drug action and offer the foundation of pharmacological investigation. Recently, the artificial intelligence (AI) technology has been utilized in various stages of drug R&D, where AI-assisted experimental methods show higher efficiency than sole experimental ones. It is a critical need to give a comprehensive review of AI applications in drug R &D for biopharmaceutical field. Methods: Relevant literatures about AI-assisted drug R&D were collected from the public databases (Including Google Scholar, Web of Science, PubMed, IEEE Xplore Digital Library, Springer, and ScienceDirect) through a keyword searching strategy with the following terms [("Artificial Intelligence" OR "Knowledge Graph" OR "Machine Learning") AND ("Drug Target Identification" OR "New Drug Development")]. Results: In this review, we first introduced common strategies and novel trends of drug R&D, followed by characteristic description of AI algorithms widely used in drug R&D. Subsequently, we depicted detailed applications of AI algorithms in target identification, lead compound identification and optimization, drug repurposing, and drug analytical platform construction. Finally, we discussed the challenges and prospects of AI-assisted methods for drug discovery. Conclusion: Collectively, this review provides comprehensive overview of AI applications in drug R&D and presents future perspectives for biopharmaceutical field, which may promote the development of drug industry.

[Thulium laser enucleation versus plasma kinetic resection of the prostate in the treatment of benign prostatic hyperplasia].

OBJECTIVE: To compare thulium laser enucleation of the prostate (ThuLEP) with plasma kinetic resection of the prostate (PKRP) in the treatment of BPH. METHODS: We retrospectively analyzed the medical records of 160 cases of BPH treated by ThuLEP (the observation group, n = 80) or PKRP (the control group, n = 80) in our hospital from January 2021 to December 2023. We recorded the operation time, bladder irrigation time, catheter retention time, hospitalization time, postoperative complications, and pre- and postoperative maximum urinary flow rate (Qmax), residual urine volume (PVR), prostate-specific antigen (PSA) and prostate volume, followed by comparison of the data obtained between the two groups of patients. RESULTS: Compared with the controls, the patients of the observation group showed significantly shorter operation time (ï¼»67.25 ± 7.24ï¼½ vs ï¼»60.10 ± 5.15ï¼½ min, P< 0.05), bladder irrigation time (ï¼»46.90 ± 10.77ï¼½ vs ï¼»43.24 ± 6.65ï¼½ h, P< 0.05), catheterization time (ï¼»5.60 ± 1.31ï¼½ vs ï¼»5.03 ± 1.24ï¼½ d, P< 0.05) and hospitalization time (ï¼»7.31 ± 2.00ï¼½ vs ï¼»6.55 ± 1.67ï¼½ d, P< 0.05), higher Qmax (ï¼»18.50 ± 1.24ï¼½ vs ï¼»20.68 ± 1.45ï¼½ ml/s, P< 0.05), lower PVR (ï¼»12.10 ± 3.53ï¼½ vs ï¼»10.82 ± 3.10ï¼½ ml, P< 0.05), PSA (ï¼»4.60 ± 0.78ï¼½ vs ï¼»3.38 ± 0.40ï¼½ µg/L, P< 0.05) and prostate volume (ï¼»25.35 ± 6.46ï¼½ vs ï¼»20.12 ± 5.13ï¼½ ml, P< 0.05) at 3 months after surgery, but no statistically significant difference in the total incidence of postoperative complications (7.50% ï¼»6/80ï¼½ vs 5.00% ï¼»4/80ï¼½, P > 0.05). CONCLUSION: ThuLEP, with its advantages of notable effect, short operation and hospitalization time, significant improvement of urinary flow dynamics and prostate function, deserves clinical promotion for the treatment of BPH.

Access to diverse carbonyl compounds by catalyst-free and photoinduced aerobic cleavage of C=N bonds.

Functional group interconversion is of great significance in organic synthesis. However, aerobic cleavage of C=N bonds to access carbonyl compounds still suffered from some limitations such as harsh reaction conditions, stoichiometric oxidants, poor substrate scope and use of toxic reagents. Herein, we report a catalyst-free and photo-induced aerobic cleavage of C=N bonds to afford diverse carbonyl compounds using oxygen from air as green oxidant. This mild methodology permits N-tosylhydrazones converted into the corresponding carbonyl compounds including ketones, amides, aldehydes and carboxylic acids, showing broad functional group tolerance and compatibility. Moreover, the gram-scale reaction and post-modification of complicated molecules proved the applicability and efficiency of this strategy. Finally, a plausible mechanism was proposed based on spectroscopic investigations and detailed mechanistic studies.

Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate.

Purpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial. Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing. Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD. Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.

Metabolomics analysis based on UHPLC-QTOF-MS/MS to explore the synthesis mechanism and culture conditions optimization of Penicillium EF-2 exopolysaccharide.

Penicillium exopolysaccharide (EPS) inhibits galactose lectins and enhances immunity. However, EPS production is low and its synthesis mechanism remains unclear. Penicillium EF-2 strains with high EPS production were selected for this study, and Penicillium fermentation conditions were subsequently improved. The optimal culture conditions were 30 g/L lactose, 6 g/L yeast extract powder, 4 d seed age, 10 % inoculation amount, 3 d of secondary fermentation time, and the final EPS yield was 3.97 g/L. UHPLC-Q-TOF-MS/MS was used to explore the mechanism of EPS synthesis at the metabolic level. Optimal carbon source: lactose and optimal nitrogen source: yeast extract can provide precursors for EPS synthesis through related metabolic pathways. Moreover, regulating the energy, vitamin, and lipid metabolic pathways created favourable conditions for EPS synthesis and secretion. These findings explain the mechanism of EPS synthesis at the metabolic level and provide a theoretical basis for optimising and industrialising EPS production.

Screening of optimal cleaning methods to reduce microplastic residues on strawberry surfaces: Characterization of microplastics in strawberry wash water.

Microplastics are widespread in facility strawberry greenhouses and can be deposited on the surface of strawberries through air currents. Investigating effective cleaning methods represents a viable strategy to reduce human ingestion of MPs. Therefore, different cleaning methods were compared: ultrasonic cleaning for 30 min, deionized water rinsing once, deionized water immersion for 30 min, and fruit immersion in washing salt for 30 min. The MPs in strawberry washing water were analyzed and compared using laser direct infrared imaging to investigate their characteristics and the optimal reduction of MPs on the surface of strawberries. The quality of the cleaning results was in the following order: water immersion > washing salt immersion > water rinsing > ultrasound. Water immersion was 1.3-2 times more effective in removing microplastics than other treatments. Furthermore, 21 polymer types were detected in the samples. Most MPs were less than 50 µm in size. The main polymers in this size range were polyamide, chlorinated polyethylene, and polyethylene terephthalate, and they mainly existed as fragments, fibers, and beads. This study provides a valuable reference for reducing human intake of microplastics through fresh fruits and vegetables.

Abnormal static and dynamic brain network connectivity associated with chronic tinnitus.

In order to comprehensively understand the changes of brain networks in patients with chronic tinnitus, this study combined static and dynamic analysis methods to explore the abnormalities of brain networks. Thirty-two patients with chronic tinnitus and 30 age-, sex- and education-matched healthy controls (HC) were recruited. Independent component analysis was used to identify resting-state networks (RSNs). Static and dynamic functional network connectivity (FNC) were performed. The temporal properties of brain network including mean dwell time (MDT), fraction time (FT) and numbers of transitions (NT) were calculated. Two-sample t test and Spearman's correlation were used for group compares and correlation analysis. Four RSNs showed abnormal FNC including auditory network (AUN), default mode network (DMN), attention network (AN) and sensorimotor network (SMN). For static analysis, tinnitus patients showed significantly decreased FNC in AUN-DMN, AUN-AN, DMN-AN, and DMN-SMN than HC [p < 0.05, false discovery rate (FDR) corrected]. For dynamic analysis, tinnitus patients showed significantly decreased FNC in DMN-AN in state 3 (p < 0.05, FDR corrected). MDT in state 3 was significantly decreased in tinnitus patients (t = 2.039, P = 0.046). In the tinnitus group, the score of tinnitus functional index (TFI) was negatively correlated with MDT and FT in state 4, and the duration of tinnitus was positively correlated with FT in state 1 and NT. Chronic tinnitus causes abnormal brain network connectivity. These abnormal brain networks help to clarify the mechanism of tinnitus generation and chronicity, and provide a potential basis for the treatment of tinnitus.

Considerations on Design and Analysis of External Control in Pediatric Oncology.

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

NUAK2 mediated regulation of Schwann Cell proliferation and migration in peripheral nerve injury via YAP.

NUAK2 is a member of the AMP-activated protein kinase (AMPK) family, which plays an essential role in cellular processes such as apoptosis, proliferation, and cell fate. Recent studies have already shown that silencing of NUAK2 blocks proliferation and promotes apoptosis of human melanoma cells and liver cancer cells. In addition, NUAK2 is involved in the development of glioblastoma via regulating the expression of cancer stem cell-related genes, and it promotes the cell cycle entry in the glioblastoma cells. However, the expression and the role of NUAK2 in the progress of peripheral nerve regeneration after injury are yet to be elucidated. We observed that NUAK2 was upregulated following distal sciatic nerve crush (SNC). Interestingly, we discovered that NUAK2 showed co-localization with S100 (Schwann cell marker). Furthermore, we found that the NUAK2 had a spatiotemporal protein expression, which was consistent with proliferating cell nuclear-antigen (PCNA). The protein level of NUAK2 and YAP was upregulated in the model of TNF-α-induced Schwann cell (SC) proliferation. Furthermore, flow cytometry analysis, CCK-8, transwell assays, and wound healing assays were all performed with the purpose of exploring the role of NUAK2 in the regulation of SC proliferation and migration. More importantly, we found that NUAK2-deficient SCs showed significantly reduced expression of Yes-associated protein (YAP). Bioinformatic analysis identified upstream regulators of NUAK2 and NUAK2-associated genes (e.g., YAP1). Finally, we investigated the recovery changes during regeneration progress through the walking track analysis. Thus, we speculated that NUAK2 was involved in biochemical and physiological responses of SCs after SNC via YAP-driven proliferation and migration, and this study determined the importance of NUAK2 as a potential target in peripheral nerve regeneration.

Soil enzyme profile analysis for indicating decomposer micro-food web.

Highly diverse exoenzymes mediate the energy flow from substrates to the multitrophic microbiota within the soil decomposer micro-food web. Here, we used a "soil enzyme profile analysis" approach to establish a series of enzyme profile indices; those indices were hypothesized to reflect micro-food web features. We systematically evaluated the shifts in enzyme profile indices in relation to the micro-food web features in the restoration of an abandoned cropland to a natural area. We found that enzymatic C:N stoichiometry and decomposability index were significantly associated with substrate availability. Furthermore, the higher Shannon diversity index in the exoenzyme profile, especially for the C-degrading hydrolase, corresponded to a greater microbiota community diversity. The increased complexity and stability of the exoenzyme network reflected similar changes with the micro-food web networks. In addition, the gross activity of the enzyme profile as a parameter for soil multifunctionality, effectively predicted the substrate content, microbiota community size, diversity, and network complexity. Ultimately, the proposed enzymic channel index was closely associated with the traditional decomposition channel indices derived from microorganisms and nematodes. Our results showed that soil enzyme profile analysis reflected very well the decomposer food web features. Our study has important implications for projecting future climate change or anthropogenic disturbance impacts on soil decomposer micro-food web features by using soil enzyme profile analysis.

5,7,4'-Trimethoxyflavone triggers cancer cell PD-L1 ubiquitin-proteasome degradation and facilitates antitumor immunity by targeting HRD1.

Targeting the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4'-trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD-L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD-L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor-infiltrating T-cell immunity and reduce the immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA-4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.

Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A.

Centromere protein A (CENP-A), a centromere-specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of ß-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis.

Photo-Deactivation Strategy for Switchable ATRP with the Assistance of Molecular Switches.

Light irradiation is an external stimulus, rapidly developed in switchable atom transfer radical polymerization (ATRP) via photo-activation methods in recent years. Herein, a photo-deactivation strategy is introduced to regulate ATRP with the assistance of photoswitchable hexaarylbiimidozole (HABI). Under visible light irradiation and in the presence of HABI, ATRP is greatly decelerated or quenched depending on the concentration of HABI. Interestingly, with visible light off, ATRP can proceed smoothly and follow a first-order kinetics. Moreover, photo-switchable ATRP alternatively with light off and on is demonstrated. Besides, the mechanism of photo-deactivation ATRP involving radical quenching is proposed in the presence of HABI.

Efficient residual network using hyperspectral images for corn variety identification.

Corn seeds are an essential element in agricultural production, and accurate identification of their varieties and quality is crucial for planting management, variety improvement, and agricultural product quality control. However, more than traditional manual classification methods are needed to meet the needs of intelligent agriculture. With the rapid development of deep learning methods in the computer field, we propose an efficient residual network named ERNet to identify hyperspectral corn seeds. First, we use linear discriminant analysis to perform dimensionality reduction processing on hyperspectral corn seed images so that the images can be smoothly input into the network. Second, we use effective residual blocks to extract fine-grained features from images. Lastly, we detect and categorize the hyperspectral corn seed images using the classifier softmax. ERNet performs exceptionally well compared to other deep learning techniques and conventional methods. With 98.36% accuracy rate, the result is a valuable reference for classification studies, including hyperspectral corn seed pictures.

Integrating single-cell and spatial analysis reveals MUC1-mediated cellular crosstalk in mucinous colorectal adenocarcinoma.

BACKGROUND: Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. METHODS: We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. RESULTS: This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. CONCLUSIONS: Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. KEY POINTS: Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.

Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.