Pathways of inhibition of filamentous sludge bulking by slowly biodegradable organic compounds.

The organic compound composition of wastewater, serves as a crucial indicator for the operational performance of activated sludge processes and has a major influence on the development of filamentous bulking in activated sludge. This study focused on the impact of typical soluble and slowly-biodegradable organic compounds, investigating the pathways through which these substrates affect the occurrence of filamentous bulking in systems operated under both high- and low-oxygen conditions. Results showed that slowly-biodegradable organic compounds lead to a concentrated distribution of microorganisms within flocs, with inward growth of filamentous bacteria. Both Tween-80 and granular starch treated systems exhibited a significant increase in protein content. The glucose system, utilizing soluble substrates, exhibited a markedly higher total polysaccharide content. Microbial communities in the Tween-80 and granular starch treated systems were characterized by a higher abundance of bacteria known to enhance sludge flocculation and settling, such as Competibacter, Xanthomonadaceae and Zoogloea. These findings are of high significance for controlling the operational performance and stability of activated sludge systems, deepening our understanding and providing a novel perspective for the improvement of wastewater treatment processes.

[Differential effects of Qingqiao and Laoqiao on bleomycin-induced pulmonary fibrosis in mice by principal component analysis].

The mechanism of alleviating bleomycin-induced pulmonary fibrosis in mice was compared between Qingqiao(Forsythiae Fructus produced with immature fruits) and Laoqiao(Forsythiae Fructus produced with mature fruits) from the pharmacodynamic correlation and composition differences. Mice were randomized into normal, model, pirfenidone(50 mg·kg~(-1)), low-and high-dose(1.3, 2.6 g·kg~(-1), respectively) Qingqiao, and low-and high-dose(1.3, 2.6 g·kg~(-1), respectively) Laoqiao groups. The mouse model of pulmonary fibrosis was established by intratracheal instillation of bleomycin, during which the survival rate and body weight changes of the mice were measured. After modeling, the lung index was calculated, and the pathological changes in the lung tissue were evaluated by hematoxylin-eosin(HE), Masson, and Sirius red staining. Transmission electron microscopy was employed to observe the ultrastructure of the lung tissue. The biochemical assay was employed to measure the levels of transforming growth factor-ß1(TGF-ß1), α-smooth muscle actin(α-SMA), E-cadherin, and hydroxyproline(HYP) in the lung tissue and interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF). The mRNA and protein levels of matrix metalloproteinase 7(MMP7), collagen Ⅰ, E-cadherin, TNF-α, vimentin, TGF-ß1, and α-SMA in the lung tissue were determined by RT-qPCR and Western blot, respectively. The expression of α-SMA in the lung tissue was detected by the immunofluorescence assay. Principal component analysis was performed to compare the effects of Qingqiao and Laoqiao in ameliorating pulmonary fibrosis. Molecular docking was employed to analyze the binding between the compounds with high content in Laoqiao and TGF-ß1. The cell-counting kit(CCK-8) assay was used to examine the effects of the active compounds on TGF-ß1-induced BEAS-2B and HFL1 cell models. The results showed that Qingqiao and Laoqiao increased the survival rate, reduced the lung index, alleviated the pathological damage and collagen deposition in the lung tissue, ameliorated the damage of lamellar bodies in alveolar epithelial type Ⅱ cells, lowered the level of IL-6 and TNF-α in the BALF, down-regulated the expression of HYP, MMP7, vimentin, collagen Ⅰ, TGF-ß1, and α-SMA, and up-regulated the expression of E-cadherin in the lung tissue of the mouse model of pulmonary fibrosis. The collagen deposition in the mouse model of pulmonary fibrosis was comprehensively evaluated by principal component analysis, and the effects of different treatments followed the trend of high-dose Laoqiao>low-dose Laoqiao>high-dose Qingqiao>low-dose Qingqiao. Molecular docking showed that hydroxytyrosol, caffeic acid, phillygenin, and(-)-lariciresinol had strong binding affinity with TGF-ß1 receptor. The results of cell experiments showed that these compounds significantly attenuated the TGF-ß1-induced damage in BEAS-2B cells and inhibited the TGF-ß1-induced proliferation of HFL1 cells. In conclusion, both Qingqiao and Laoqiao were effective in ameliorating bleomycin-induced pulmonary fibrosis in mice. Laoqiao was superior to Qingqiao in reducing collagen deposition, which might be attributed to the higher content of hydroxytyrosol, caffeic acid, phillygenin, and(-)-lariciresinol in Laoqiao than in Qingqiao.

Understanding the Hierarchical Structure of Collagen Fibers of the Human Periodontal Ligament: Implications for Biomechanical Characteristics.

The periodontal ligament (PDL) is a unique fibrous connective tissue that regulates periodontal homeostasis mechanisms. Its biomechanical properties primarily reside in the hierarchical and non-uniform collagenous network. This study aimed to investigate the region-specific structure and composition of collagen fibers in the PDL at various scales and to explore their relationship with mechanical properties in a split-mouth design. Fresh human cadaver transverse PDL specimens of maxillary anterior teeth were categorized into cervical, middle, and apical groups. These specimens were analyzed via Masson's trichrome staining, scanning electron microscopy, picrosirius red (PSR) staining, three-dimensional (3D) reconstruction, Raman spectroscopy, and uniaxial tensile test. Statistical analyses were performed to compare the structural, compositional, and tensile properties among the groups. Notably, the middle PDL samples exhibited superior tensile strength and higher fiber area fraction than the other two transverse sections. Despite a higher mineral-to-matrix ratio and a different collagen secondary structure, the apical PDL demonstrated a relatively weaker tensile strength, possibly associated with its discovered sparser collagen fiber areal fraction. The cervical region, characterized by a mediocre fiber areal fraction, displayed diminished tensile strength. The 3D reconstructed collagenous network model and PSR staining exposed the fiber interaction and the micropores. Microscale porosity and variations in collagen secondary structure, particularly in the apical region, suggest adaptive mechanisms for accommodating compressive forces and maintaining functional integrity. Variance in the tensile properties of samples in different force directions indicated the significant influence of fiber orientation and root level on tissue mechanics. STATEMENT OF SIGNIFICANCE: : This study provides critical insights into the biomechanical and structural properties of the human periodontal ligament (PDL), particularly focusing on the underexplored anterior teeth. Through advanced techniques like SEM, histological staining, 3D reconstruction, Raman spectroscopy, and tensile testing, we reveal significant regional variations in PDL collagen organization, composition, and biomechanical properties. Our findings address a crucial knowledge gap concerning the material mechanics of the PDL, offering a foundational understanding for future periodontal tissue engineering and biomimetic material development. This multi-scale analysis underscores the importance of both mesoscale structural characteristics and nanoscale molecular structures in maintaining PDL mechanical integrity.

Non-invasive imaging innovation: FFR-CT combined with plaque characterization, safeguarding your cardiac health.

Studies have shown that high-risk plaque features (including thin fibrous caps, lipid-rich cores, large plaque volumes, and intraplaque microcalcifications) are closely associated with the occurrence of acute coronary events. CT-derived fractional flow reserve (CT-FFR) is a non-invasive imaging post-processing technique that utilizes artificial intelligence to analyze data obtained from conventional coronary CT angiography (CCTA). FFR-CT technology offers the hemodynamic assessment of coronary lesions, aiding in the prediction of potential cardiovascular risks. This review summarizes the latest research progress on the complex relationship between FFR-CT, plaque characteristics, and hemodynamics, closely linking plaque volume, composition, and distribution with the clinical significance of coronary artery stenosis. It is hoped that these research findings will provide valuable guidance for clinicians, promoting the application of CT in the non-invasive detection of vulnerable plaques, thereby more effectively preventing and managing coronary artery disease. In the future, further optimization of FFR-CT technology and expansion of its clinical application are expected to significantly reduce the incidence and mortality of coronary artery disease, offering new hope for the prevention and treatment of cardiovascular diseases.

The NSCLC immunotherapy response predicted by tumor-infiltrating T cells via a non-invasive radiomic approach.

Introductions: Identifying patients with non-small cell lung cancer (NSCLC) who are optimal candidates for immunotherapy is a cornerstone in clinical decision-making. The tumor immune microenvironment (TIME) is intricately linked with both the prognosis of the malignancy and the efficacy of immunotherapeutic interventions. CD8+ T cells, and more specifically, tissue-resident memory CD8+ T cells [CD8+ tissue-resident memory T (TRM) cells] are postulated to be pivotal in orchestrating the immune system's assault on tumor cells. Nevertheless, the accurate quantification of immune cell infiltration-and by extension, the prediction of immunotherapeutic efficacy-remains a significant scientific frontier. Methods: In this study, we introduce a cutting-edge non-invasive radiomic model, grounded in TIME markers (CD3+ T, CD8+ T, and CD8+ TRM cells), to infer the levels of immune cell infiltration in NSCLC patients receiving immune checkpoint inhibitors and ultimately predict their response to immunotherapy. Data from patients who had surgical resections (cohort 1) were employed to construct a radiomic model capable of predicting the TIME. This model was then applied to forecast the TIME for patients under immunotherapy (cohort 2). Conclusively, the study delved into the association between the predicted TIME from the radiomic model and the immunotherapeutic outcomes of the patients. Result: For the immune cell infiltration radiomic prediction models in cohort 1, the AUC values achieved 0.765, 0.763, and 0.675 in the test set of CD3+ T, CD8+ T, and CD8+ TRM, respectively. While the AUC values for the TIME-immunotherapy predictive value were 0.651, 0.763, and 0.829 in the CD3-immunotherapy response model, CD8-immunotherapy response model, and CD8+ TRM-immunotherapy response model in cohort 2, respectively. The CD8+ TRM-immunotherapy model exhibited the highest predictive value and was significantly better than the CD3-immunotherapy model in predicting the immunotherapy response. The progression-free survival (PFS) analysis based on the predicted levels of CD3+ T, CD8+ T, and CD8+ TRM immune cell infiltration showed that the CD8+ T cell infiltration level was an independent factor (P=0.014, HR=0.218) with an AUC value of 0.938. Discussion: Our empirical evidence reveals that patients with substantial CD8+ T cell infiltration experience a markedly improved PFS compared with those with minimal infiltration, asserting the status of the CD8+ T cell as an independent prognosticator of PFS in the context of immunotherapy. Although CD8+ TRM cells demonstrated the greatest predictive accuracy for immunotherapy response, their predictive strength for PFS was marginally surpassed by that of CD8+ T cells. These insights advocate for the application of the proposed non-invasive radiomic model, which utilizes TIME analysis, as a reliable predictor for immunotherapy outcomes and PFS in NSCLC patients.

Added value of histogram analysis of intravoxel incoherent motion and diffusion kurtosis imaging for the evaluation of complete response to neoadjuvant therapy in locally advanced rectal cancer.

OBJECTIVE: To evaluate how intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram analysis contribute to assessing complete response (CR) to neoadjuvant therapy (NAT) in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: In this prospective study, participants with LARC, who underwent NAT and subsequent surgery, with adequate MR image quality, were enrolled from November 2021 to March 2023. Conventional MRI (T2WI and DWI), IVIM, and DKI were performed before NAT (pre-NAT) and within two weeks before surgery (post-NAT). Image evaluation was independently performed by two experienced radiologists. Pathological complete response (pCR) was used as the reference standard. An IVIM-DKI-added model (a combination of IVIM and DKI histogram parameters with T2WI and DWI) was constructed. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of conventional MRI and the IVIM-DKI-added model. RESULTS: A total of 59 participants (median age: 58.00 years [IQR: 52.00, 62.00]; 38 [64%] men) were evaluated, including 21 pCR and 38 non-pCR cases. The histogram parameters of DKI, including skewness of kurtosis post-NAT (post-KSkewness) and root mean squared of change ratio of diffusivity (Δ%DDKI-root mean squared), were entered into the IVIM-DKI-added model. The area under the ROC curve (AUC) of the IVIM-DKI-added model for assessing CR to NAT was significantly higher than that of conventional MRI (0.855 [95% CI: 0.749-0.960] vs 0.685 [95% CI: 0.565-0.806], p < 0.001). CONCLUSION: IVIM and DKI provide added value in the evaluation of CR to NAT in LARC. KEY POINTS: Question The current conventional imaging evaluation system lacks adequacy for assessing CR to NAT in LARC. Findings Significantly improved diagnostic performance was observed with the histogram analysis of IVIM and DKI in conjunction with conventional MRI. Clinical relevance IVIM and DKI provide significant value in evaluating CR to NAT in LARC, which bears significant implications for reducing surgical complications and facilitating organ preservation.

Interplay of ferroptosis, cuproptosis, and PANoptosis in cancer treatment-induced cardiotoxicity: Mechanisms and therapeutic implications.

With the prolonged survival of individuals with cancer, the emergence of cardiovascular diseases (CVD) induced by cancer treatment has become a significant concern, ranking as the second leading cause of death among cancer survivors. This review explores three distinct types of programmed cell death (PCD): ferroptosis, cuproptosis, and PANoptosis, focusing on their roles in chemotherapy-induced cardiotoxicity. While ferroptosis and cuproptosis are triggered by excess iron and copper (Cu), PANoptosis is an inflammatory PCD with features of pyroptosis, apoptosis, and necroptosis. Recent studies reveal intricate connections among these PCD types, emphasizing the interplay between cuproptosis and ferroptosis. Notably, the role of intracellular Cu in promoting ferroptosis through GPX4 is highlighted. Additionally, ROS-induced PANoptosis is influenced by ferroptosis and cuproptosis, suggesting a complex interrelationship. This review provides insights into the molecular mechanisms of these PCD modalities and their distinct contributions to chemotherapy-induced cardiotoxicity. Furthermore, we discuss the potential application of cardioprotective drugs in managing these PCD types. This comprehensive analysis aims to advance the understanding, diagnosis, and therapeutic strategies for cardiotoxicity associated with cancer treatment.

nQuant Enables Precise Quantitative N-Glycomics.

N-glycosylation is a highly heterogeneous post-translational modification that modulates protein function. Defects in N-glycosylation are directly linked to various human diseases. Despite the importance of quantifying N-glycans with high precision, existing glycoinformatics tools are limited. Here, we developed nQuant, a glycoinformatics tool that enables label-free and isotopic labeling quantification of N-glycomics data obtained via LC-MS/MS, ensuring a low false quantitation rate. Using the label-free quantification module, we profiled the N-glycans released from purified glycoproteins and HEK293 cells as well as the dynamic changes of N-glycosylation during mouse corpus callosum development. Through the isotopic labeling quantification module, we revealed the dynamic changes of N-glycans in acute promyelocytic leukemia cells after all-trans retinoic acid treatment. Taken together, we demonstrate that nQuant enables fast and precise quantitative N-glycomics.

Subtraction and Addition of Propagating Photons by Two-Level Emitters.

Coherent manipulation of quantum states of light is key to photonic quantum information processing. In this Letter, we show that a passive two-level nonlinearity suffices to implement non-Gaussian quantum operations on propagating field modes. In particular, the collective light-matter interaction can efficiently extract a single photon from a multiphoton input wave packet to an orthogonal temporal mode. We accurately describe the single-photon subtraction process by elements of an intuitive quantum-trajectory model. By employing this process, quantum information protocols gain orders of magnitude improved efficiency over heralded schemes with linear optics. The reverse process can be used to add photons one by one to a single wave packet mode and compose arbitrarily large Fock states with a finite total success probability >96.7%.

Mechanistic insights into Fe3O4-mediated inhibition of H2S gas production in sludge anaerobic digestion.

The addition of iron-based conductive materials has been extensively validated as a highly effective approach to augment methane generation from anaerobic digestion (AD) process. In this work, it was additionally discovered that Fe3O4 notably suppressed the production of hazardous H2S gas during sludge AD. As the addition of Fe3O4 increased from 0 to 20 g/L, the accumulative H2S yields decreased by 89.2 % while the content of element sulfur and acid volatile sulfide (AVS) respectively increased by 55.0 % and 30.4 %. Mechanism analyses showed that the added Fe3O4 facilitated sludge conductive capacity, and boosted the efficiency of extracellular electron transfer, which accelerated the bioprocess of sulfide oxidation. Although Fe3O4 can chemically oxidize sulfide to elemental sulfur, microbial oxidation plays a major role in reducing H2S accumulation. Moreover, the released iron ions reacted with soluble sulfide, which promoted the chemical equilibrium of sulfide species from H2S to metal sulfide. Microbial analysis showed that some SRBs (i.e., Desulfomicrobium and Defluviicoccus) and SOB (i.e., Sulfuritalea) changed into keystone taxa (i.e., connectors and module hubs) in the reactor with Fe3O4 addition, showing that the functions of sulfate reduction and sulfur oxidation may play important roles in Fe3O4-present system. Fe3O4 presence also increased the content of functional genes encoding sulfide quinone reductase and flavocytochrome c sulfidedehydrogenase (e.g., Sqr and Fcc) that could oxidize sulfide to sulfur. The impact of other iron-based conductive material (i.e., zero-valent iron) was also verified, and the results showed that it could also significantly reduce H2S production. These findings provide new insights into the effect of iron-based conductive materials on anaerobic process, especially sulfur conversion.

Cooperative application of transcriptomics and ceRNA hypothesis: lncRNA-00742/miR-116 targets CD74 to mediate vanadium-induced mitochondrial apoptosis in duck liver.

Vanadium (V) is a poisonous metallic environmental pollutant which poses hazard to the animal health of the liver. Competitive endogenous ribonucleic acids (ceRNAs) are essential elements of mitochondrial function and apoptosis, and their effects have been associated with the metal toxicity mechanism. However, the specific mechanism of ceRNAs in V-induced mitochondrial apoptosis in the liver has not been adequately investigated. Hence, we established an in vivo model of ducks exposed to V for 44 days and an in vitro model of V exposure duck hepatocyte knockdown/overexpression. Results showed that V exposure triggered the differential expression of 1106 lncRNAs and 11 miRNAs in the liver. Besides, we established the lncRNA-00742/miR-116/CD74 regulatory network by the dual luciferase reporter gene. Our results also found that V induced mitochondrial injury and up-regulated the expression levels of mitochondrial apoptosis-related factors. Furthermore, knockdown of miR-116 attenuated V-induced mitochondrial injury and apoptosis in hepatocytes. In contrast, overexpression of miR-116 and knockdown of CD74 exacerbated mitochondrial injury and apoptosis. BTZO-1 upregulated the CD74 level and alleviated V-induced mitochondrial apoptosis. In summary, V induced mitochondrial damage and apoptosis in duck liver by activating the lncRNA-00742/miR-116/CD74 axis. This research firstly revealed the mechanism of lncRNA-related ceRNAs regulating V-induced mitochondrial apoptosis.

Significance of humic matters-soil mineral interactions for environmental remediation: A review.

Industrial and human activities have led to serious soil and water pollution. Traditional remediation techniques have problems such as high treatment costs and the tendency to cause secondary pollution. Soil minerals and humic matters are common active components in soils. Both play vital roles and are frequently bound together to form humic matters-mineral complexes, which are considered sustainable and eco-friendly materials for environmental remediation and improvement. However, due to the complexity of humic matters-mineral interactions and the wide variation in the removal of different pollutants, there is a lack of research in this area. This paper provides a comprehensive introduction and summary of the interaction mechanisms between humic matters and typical soil minerals such as layered phosphate minerals and iron oxides, and their applications in environmental remediation, especially for the treatment of heavy metals (lead, mercury, chromium and cadmium) and organic pollutants (antibiotics, pesticides and polycyclic aromatic hydrocarbons) in water and soil. The humic matters-mineral complex can reduce the toxicity and migration rate of pollutants through adsorption, electrostatic attraction, together with H-bonding and hydrophobic interactions, reducing the harm of these pollutants to soil and water environments and realizing the efficient remediation of soil and water environments. And compared with the traditional treatment technology, this method is more green and environmental protection, and the treatment cost is greatly reduced. Finally, the deficiencies of using humic matters-mineral complex to achieve soil and water remediation were summarized and also proposed directions for future endeavors as well as concrete measures.

Aberrant overexpression of myosin 1b in glioblastoma promotes angiogenesis via VEGF-myc-myosin 1b-Piezo1 axis.

Glioblastoma (GBM) is the most aggressive intracranial malignancy with poor prognosis. Enhanced angiogenesis is an essential hallmark of GBM, which demonstrates extensive microvascular proliferation and abnormal vasculature. Here, we uncovered the key role of myosin 1b in angiogenesis and vascular abnormality in GBM. Myosin 1b is upregulated in GBM endothelial cells (ECs) compared to the paired non-malignant brain tissue. In our study, we found that myosin 1b promotes migration, proliferation and angiogenesis of human/mouse brain ECs. We also found that myosin 1b expression in ECs can be regulated by vascular endothelial growth factor (VEGF) signaling through myc. Moreover, myosin 1b promotes angiogenesis via Piezo1 by enhancing Ca2+ influx, in which process VEGF can be the trigger. In conclusion, our results identified myosin 1b as a key mediator in promoting angiogenesis via mechanosensitive ion channel component 1 (Piezo1) and suggested that VEGF/myc signaling pathway could be responsible for driving the changes of myosin 1b overexpression in GBM ECs.

Maternal High-Fat Diet Exacerbates Epicutaneous Sensitization and Oral Challenge-Induced Food Allergy to Ovalbumin in Offspring Mice.

Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1ß) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.

Dynamically Regulating Homologous Recombination Enables Precise Genome Editing in Ogataea polymorpha.

Methylotrophic yeast Ogataea polymorpha has become a promising cell factory due to its efficient utilization of methanol to produce high value-added chemicals. However, the low homologous recombination (HR) efficiency in O. polymorpha greatly hinders extensive metabolic engineering for industrial applications. Overexpression of HR-related genes successfully improved HR efficiency, which however brought cellular stress and reduced chemical production due to constitutive expression of the HR-related gene. Here, we engineered an HR repair pathway using the dynamically regulated gene ScRAD51 under the control of the l-rhamnose-induced promoter PLRA3 based on the previously constructed CRISPR-Cas9 system in O. polymorpha. Under the optimal inducible conditions, the appropriate expression level of ScRAD51 achieved up to 60% of HR rates without any detectable influence on cell growth in methanol, which was 10-fold higher than that of the wild-type strain. While adopting as the chassis strain for bioproductions, the dynamically regulated recombination system had 50% higher titers of fatty alcohols than that static regulation system. Therefore, this study provided a feasible platform in O. polymorpha for convenient genetic manipulation without perturbing cellular fitness.

Celastrol induces DNA damage and cell death in BCR-ABL T315I-mutant CML by targeting YY1 and HMCES.

BACKGROUND: Chronic myeloid leukemia (CML) is driven primarily by the constitutively active BCR-ABL fusion oncoprotein. Although the development of tyrosine kinase inhibitors has markedly improved the prognosis of CML patients, it remains a significant challenge to overcome drug-resistant mutations, such as the T315I mutation of BCR-ABL, and achieve treatment-free remission in the clinic. PURPOSE: The identification of new intervention targets beyond BCR-ABL could provide new perspectives for future research and therapeutic intervention. A network pharmacology analysis was conducted to identify the most promising natural product with anti-CML activity. Celastrol was selected for further analysis to gain insights into its mechanism of action (MoA), with the aim of identifying potential new intervention targets for BCR-ABL T315I-mutant CML. METHODS: Transcriptomic and proteomic analyses were conducted to systematically investigate the molecular MoA of celastrol in K562T315I cells. To identify the target proteins of celastrol, mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) was carried out, followed by validations with genetic knockdown and overexpression, cell proliferation assay, comet assay, Western blotting, celastrol probe-based in situ labeling and pull-down assay, molecular docking, and biolayer interferometry. RESULTS: Our multi-omics analyses revealed that celastrol primarily induces DNA damage accumulation and the unfolded protein response in K562T315I cells. Among the twelve most potential celastrol targets, experimental evidence demonstrated that the direct interaction of celastrol with YY1 and HMCES increases the levels of DNA damage, leading to cell death. CONCLUSION: This study represents the first investigation utilizing a proteome-wide label-free target deconvolution approach, MS-CETSA, to identify the protein targets of celastrol. This study also develops a new systems pharmacology strategy. The findings provide new insights into the multifaceted mechanisms of celastrol and, more importantly, highlight the potential of targeting proteins in DNA damage and repair pathways, particularly YY1 and HMCES, to combat drug-resistant CML.

Performance evaluation of the glycated hemoglobin A1c analyzer for point-of-care testing compared with laboratory-based devices: a multicenter validation study.

In this dual-center study, we assessed the BioHermes A1C EXP M13 system for point-of-care (POC) HbA1c testing against two NGSP-certified HPLC instruments, the Bio-Rad D100 and Tosoh G8. Analyzing 605 samples, we evaluated the A1C EXP's reproducibility, sensitivity, specificity and impact of anemia on HbA1c measurements. The device showed excellent reproducibility with CVs under 2.4% and high sensitivity and specificity for diabetes diagnosis-98.1% and 96.8% against D100, and 97.1% and 96.7% against G8. Passing-Bablok regression confirmed a close correlation between A1C EXP and the HPLC instruments, with equations y = 0.10625 + 0.9688x (D100) and y = 0.0000 + 0.1000x (G8), and Bland-Altman plots indicated mean relative differences of -1.4% (D100) and -0.4% (G8). However, in anemic samples, A1C EXP showed a negative bias compared to HPLC devices, suggesting that anemia may affect the accuracy of HbA1c results. The study indicates that A1C EXP is a reliable POC alternative to laboratory assays, albeit with considerations for anemic patients.

3D indoor area recognition for personnel security using integrated UWB and barometer approach.

Real-time location tracking is essential for personal security in industrial scenes, e.g. monitoring worker safety in power substations. Ultra wideband (UWB) technology is suitable for indoor positioning thanks to its high penetration capability, high ranging accuracy and low power consumption. However, UWB based trilateration positioning requires high workload for field deployment of base stations. Indoor complex topology results in multipath and non-line of sight (NLOS) conditions of UWB signals, and degrades the positioning performance in terms of accuracy and reliability. This paper proposes a three-dimensional (3D) area recognition solution by integrating UWB time of flight (TOF) ranging and barometer measurements. The proposed solution utilizes a multi-tier distributed joint probabilistic inference model, which accomplishes the indoor 3D area recognition exploiting multiple clustering and prediction algorithms of machine learning. The field experiments showed that the proposed method can achieve an accuracy of 3D area recognition of more than 99.2%. The proposed method improves the computing efficiency by 93%. The errors of improved differential barometric height estimation method are less than 1 m, which means a success rate of 100% for floor identification, given a floor separation of 3-4 m. The proposed solution is suitable for personnel security applications of industrial scenes, which requires reliable real-time area information rather than just coordinates.

Characterization of sequence variations in the extended flanking regions using massively parallel sequencing in 21 A-STRs and 21 Y-STRs.

In forensic genetics, utilizing massively parallel sequencing (MPS) to analyze short tandem repeats (STRs) has demonstrated several advantages compared to conventional capillary electrophoresis (CE). Due to the current technical limitations, although flanking region polymorphisms had been mentioned in several previous studies, most studies focused on the core repeat regions of STRs or the variations in the adjacent flanking regions. In this study, we developed an MPS system consisting of two sets of multiplex PCR systems to detect not only the STR core repeat regions but also to observe variants located at relatively distant positions in the flanking regions. The system contained 42 commonly used forensic STRs, including 21 autosomal STRs (A-STRs) and 21 Y-chromosomal STRs (Y-STRs), and a total of 350 male individuals from a Chinese Han population were genotyped. The length and sequence variants per locus were tallied and categorized based on length (length-based, LB), sequence without flanking region (core repeat regions sequence-based, RSB), and sequence with flanking region (core repeat and flanking regions sequence-based, FSB), respectively. Allele frequencies, Y-haplotype frequencies, and forensic parameters were calculated based on LB, RSB, and FSB, respectively, to evaluate the improvement in discrimination power, heterozygosity, and effectiveness of forensic systems. The results suggested the sequence variations have more influence on A-STRs and could improve the identification ability of MPS-STR genotyping. Concordance between MPS and CE methods was confirmed by using commercial CE-based STR kits. The impact of flanking region variations on STR genotype analysis and potential factors contributing to discordances were discussed. A total of 58 variations in the flanking regions (53 SNPs/SNVs and 5 InDels) were observed and most variations (48/58) were distributed in A-STRs. In summary, this study delved deeper into the genetic information of forensic commonly used STR and advanced the application of massively parallel sequencing in forensic genetics.

Network Pharmacology and Experimental Analysis to Explore the Effect and Mechanism of Modified Buyang Huanwu Decoction in the Treatment of Diabetic Nephropathy.

Purpose: Preventing and treating diabetic nephropathy (DN) are global challenges due to the complexity and diversity of its causes and manifestations. It is important to find effective medications to treat DN. Patients and Methods: Gene expression files of DN were downloaded from the GEO database to identify the differentially expressed genes. Network pharmacology and molecular docking were used to explore the possible mechanisms of modified Buyang Huanwu Decoction (mBHD) in treating DN. Biochemical, histopathological, and real-time PCR analyses were conducted in both in vivo and in vitro DN models to investigate the effects of mBHD. Results: A total of 336 active ingredients and 124 potential targets of mBHD associated with DN were identified. Among them, 8 hub genes were found to be important targets for mBHD in treating DN and were significantly correlated with the infiltration status of six immune cells. Partially, the active ingredients of mBHD demonstrated good stability in binding to CASP3 and TP53. mBHD treatment significantly reduced levels of total cholesterol, triglyceride, blood urea nitrogen, serum creatinine, and microalbumin in db/db mice. HE and Masson's staining results showed that mBHD attenuated renal injury in db/db mice. Additionally, mBHD treatment could significantly alter the expression of CASP3, CCL2, TP53, ALB, and HMOX1. Conclusion: mBHD may be involved in the treatment of DN through multiple ingredients, targets, and pathways. In addition, mBHD could alleviate renal injury in db/db mice, possibly involving CASP3, CCL2, TP53, ALB, and HMOX1.