Sialosides containing C8-modified sialic acids are challenging synthetic targets but potentially useful probes for diagnostic substrate profiling of sialidases and elucidating the binding specificity of sialic acid-interacting proteins. Here, we demonstrate efficient chemoenzymatic methods for synthesizing para-nitrophenol-tagged a2-3- and a2-6-linked sialyl galactosides containing C8-acetamido, C8-azido, or C8-amino derivatized N-acetylneuraminic acid (Neu5Ac). High-throughput substrate specificity studies showed that the C8-modification of sialic acid significantly changes its recognition by sialidases from humans, various bacteria, and different influenza A and B viruses. Sialosides carrying Neu5Ac with a C8-azido modification were generally well tolerated by all the sialidases we tested, whereas sialosides containing C8-acetamido-modified Neu5Ac were only cleaved by selective bacterial sialidases. In contrast, sialosides with C8-amino-modified Neu5Ac were cleaved by a combination of selective bacterial and influenza A virus sialidases. These results indicate that sialosides terminated with a C8-amino or C8-acetamido-modified sialic acid can be used with other sialosides for diagnostic profiling of disease-causing sialidase-producing pathogens.
OBJECTIVE: Preeclampsia (PE) is a severe complication of unclear pathogenesis associated with pregnancy. This research aimed to elucidate the properties of immune cell infiltration and potential biomarkers of PE based on bioinformatics analysis. MATERIALS AND METHODS: Two PE datasets were imported from the Gene ExpressioOmnibus (GEO) and screened to identify differentially expressed genes (DEGs). Significant module genes were identified by weighted gene co-expression network analysis (WGCNA). DEGs that interacted with key module genes (GLu-DEGs) were analyzed further by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. The diagnostic value of the genes was assessed using receiver operating characteristic (ROC) curves and protein-protein interaction (PPI) networks were constructed using GeneMANIA, and GSVA analysis was performed using the MSigDB database. Immune cell infiltration was analyzed using the TISIDB database, and StarBase and Cytoscape were used to construct an RBP-mRNA network. The identified hub genes were validated in two independent datasets. For further confirmation, placental tissue from healthy pregnant women and women with PE were collected and analyzed using both RT-qPCR and immunohistochemistry. RESULTS: A total of seven GLu-DEGs were obtained and were found to be involved in pathways associated with the transport of sulfur compounds, PPAR signaling, and energy metabolism, shown by GO and KEGG analyses. GSVA indicated significant increases in adipocytokine signaling. Furthermore, single-sample Gene Set Enrichment Analysis (ssGSEA) indicated that the levels of activated B cells and T follicular helper cells were significantly increased in the PE group and were negatively correlated with GLu-DEGs, suggesting their potential importance. CONCLUSION: In summary, the results showed a correlation between glutamine metabolism and immune cells, providing new insights into the understandingPE pathogenesis and furnishing evidence for future advances in the treatment of this disease.
Gene Regulatory Networks , Glutamine , Pre-Eclampsia , Protein Interaction Maps , Humans , Pre-Eclampsia/genetics , Pre-Eclampsia/immunology , Female , Pregnancy , Protein Interaction Maps/genetics , Glutamine/metabolism , Computational Biology/methods , Gene Ontology , Gene Expression Profiling , Adult , Placenta/metabolism , Placenta/immunology
The semiconductors industry has put its eyes on two-dimensional (2D) materials produced by chemical vapour deposition (CVD) because they can be grown at the wafer level with small thickness fluctuations, which is necessary to build electronic devices and circuits. However, CVD-grown 2D materials can contain significant amounts of lattice distortions, which degrades the performance at the device level and increases device-to-device variability. Here we statistically analyse the quality of commercially available CVD-grown hexagonal boron nitride (h-BN) from the most popular suppliers. h-BN is of strategic importance because it is one of the few insulating 2D materials, and can be used as anti-scattering substrate and gate dielectric. We find that the leakage current and electrical homogeneity of all commercially available CVD h-BN samples are significantly worse than those of mechanically exfoliated h-BN of similar thickness. Moreover, in most cases the properties of the CVD h-BN samples analysed don't match the technical specifications given by the suppliers, and the sample-to-sample variability is unsuitable for the reproducible fabrication of capacitors, transistors or memristors in different batches. In the short term, suppliers should try to provide accurate sample specifications matching the properties of the commercialized materials, and researchers should keep such inaccuracies in mind; and in the middle term suppliers should try to reduce the density of defects to enable the fabrication of high-performance devices with high reliability and reproducibility.
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
OBJECTIVE: To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). METHODS: According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. RESULTS: Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). CONCLUSION: STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.
Multivalent pneumococcal vaccines have been developed successfully to combat invasive pneumococcal diseases (IPD) and reduce the associated healthcare burden. These vaccines employ pneumococcal capsular polysaccharides (PnPs), either conjugated or unconjugated, as antigens to provide serotype-specific protection. Pneumococcal capsular polysaccharides used for vaccine often contain residual levels of cell wall polysaccharides (C-Ps), which can generate a non-serotype specific immune response and complicate the desired serotype-specific immunity. Therefore, the C-P level in a pneumococcal vaccine needs to be controlled in the vaccine process and the anti C-P responses need to be dialed out in clinical assays. Currently, two types of cell-wall polysaccharide structures have been identified: a mono-phosphocholine substituted cell-wall polysaccharide C-Ps1 and a di-phosphocholine substituted C-Ps2 structure. In our effort to develop a next-generation novel pneumococcal conjugate vaccine (PCV), we have generated a monoclonal antibody (mAb) specific to cell-wall polysaccharide C-Ps2 structure. An antibody-enhanced HPLC assay (AE-HPLC) has been established for serotype-specific quantification of pneumococcal polysaccharides in our lab. With the new anti C-Ps2 mAb, we herein extend the AE-HPLC assay to the quantification and identification of C-Ps2 species in pneumococcal polysaccharides used for vaccines.
BACKGROUND: Many studies have explored the impact of body mass index (BMI) on stroke prognosis, yet findings remain inconsistent. AIMS: The aims of this study were to conduct a systematic review and meta-analyses to summarize the existing evidence on BMI and stroke outcomes. METHODS: PubMed, Web of Science, Embase, The Cochrane Library, CNKI, CBM, Wanfang Database, and VIP Database were systematically searched from inception to 1 January 2023. Cohort studies were included if they reported on a population of patients with stroke, evaluated BMI on stroke outcomes (mortality/recurrence/score of modified Rankin scale (mRs)), and reported original data. Data extraction and quality assessment were independently undertaken by two reviewers. Stata 16.0 software was used for meta-analysis. RESULTS: Thirty-two studies involving 330,353 patients (5 Chinese language articles) were included in the analysis. The proportion of underweight, overweight, and obese patients was 1.85%, 18.2%, and 15.6%, respectively. Compared with normal weight, being underweight was associated with an increased risk of mortality (relative risk (RR) = 1.78, 95% confidence interval (CI) = 1.60-1.96), poor functional outcomes defined as modified Rankin scale ⩾ 3 (RR = 1.33, 95% CI = 1.22-1.45), and stroke recurrence (RR = 1.19, 95% CI = 1.04-1.37). Being overweight but not obese was associated with reduced mortality (RR = 0.81, 95% CI = 0.74-0.89) and better functional outcomes (RR = 0.92, 95% CI = 0.89-0.96), but did not alter the risk of stroke recurrence (RR = 1.03, 95% CI = 0.90-1.17). Obesity was associated with lower risk of mortality (RR = 0.76, 95% CI = 0.72-0.81) and better functional outcomes (RR = 0.89, 95% CI = 0.84-0.94). CONCLUSIONS: Our findings indicate that in patients with stroke, being underweight is associated with an increased risk of mortality, poor functional outcomes, and stroke recurrence. In contrast, being overweight but not obese, or being obese, was associated with a decreased risk of mortality and better functional outcomes. This is consistent with the obesity paradox in stroke, whereby obesity increases stroke risk in the general population but is associated with improved outcome in patients suffering stroke.
The accurate determination of the free nicotine content in cigarette smoke is crucial for assessing cigarette quality, studying harm and addiction, and reducing tar levels. Currently, the determination of free nicotine in tobacco products primarily relies on methods such as pH calculation, nuclear magnetic resonance (NMR) spectroscopy, headspace solid-phase microextraction (HS-SPME), and traditional solvent extraction. However, these methods have limitations that restrict their widespread application. In this study, the free nicotine in cigarette smoke was directly extracted by using cyclohexane according to the traditional solvent extraction method and detected via gas chromatography-mass spectrometry. Compared with the traditional two-phase solvent extraction, our experimental method is easy to execute and eliminates the influence of aqueous solutions on the original distribution of nicotine in cigarette smoke particulate matter. Furthermore, the presence of protonated nicotine in tobacco does not affect the determination. Compared with HS-SPME and NMR spectroscopy, our approach, which involves solvent extraction followed by chromatographic separation and instrumental detection, offers simplicity, improved precision, better detection limits, and reduced interference during the instrumental detection stage. The standard addition recoveries in the conducted experiment ranged from 96.2% to 102.5%. The limit of detection was 2.8 µg/cig, and the correlation coefficient (R2) for the quadratic regression of the standard curve exceeded 0.999. The relative standard deviation for parallel samples was between 1.7% and 3.4% (n = 5), fully meeting the requirements for the determination of free nicotine in cigarette smoke. Analysis of cigarette samples from 38 commercially available brands revealed that the content of free nicotine ranged from 0.376 to 0.716 mg/cig, with an average of 0.540 mg/cig, and free nicotine accounted for 39.1%-88.8% of the total nicotine content.
Caramel color is a widely used food pigment, and 2-Acetyl-4-tetrahydroxybutylimidazole (THI) is a by-products of Class III caramel color. Some studies have shown that THI can reduce the number of peripheral blood lymphocytes. However, the comprehensive mechanism of THI immunotoxicity requires further study. In this study, the effects of THI on lymphocyte count, humoral immunity, cellular immunity and nonspecific immunity were determined and the effect of the nutritional status of VB6 on THI immunotoxicity was evaluated. Female BALB/c mice were divided into 3 groups and fed chow containing different doses of VB6: VB6-normal (6mg/kg VB6), VB6-deprived (0.5mg/kg VB6) or VB6-enhanced (12mg/kg VB6) feed. Each group was further divided into 4 subgroups and treated with THI (0.5, 2.5 or 12.5mg/kg bw) or the solvent control by gavage for 30 days. The thymic cortical thickness was measured with ViewPoint; the proportions of major immune cells and T cells in peripheral blood and tissues were detected via flow cytometry; the transformation and proliferation abilities of T and B cells were detected via T and B lymphocyte proliferation assays; NK cell activity was assessed via lactate dehydrogenase assays; humoral immune function was assessed via plaque-forming cell assays; and the immune function of T lymphocytes was assessed via delayed type hypersensitivity assays. The results showed that compared with those in the corresponding control group, the white blood cell count and lymphocyte count decreased significantly in all the VB6-deprived groups, in the 2.5 and 12.5mg/kg VB6 groups, and in the 12.5mg/kg VB6-enhanced group. With increasing THI dose, the thymic cortical layer became thinner. In the thymus, THI increased the proportions of CD3+ T cells and mature CD8+ T cells and decreased the proportions of immature double-positive, double-negative T cells and CD69-expressing lymphocytes. The proportions of naïve T cells and Tcm (central memory T) cells related to homing decreased. The proportion of mature T cells in the spleen decreased significantly. The proliferation of T cells stimulated by ConA decreased after THI exposure. VB6-deficient mice were more sensitive to THI immunotoxicity, and supplementation with VB6 had a certain protective effect on these mice. The results of the PFC and NK cell activity assays indicated that THI exposure might not affect humoral immune or innate immune function.
Schistosoma infection is one of the major causes of liver fibrosis. Emerging roles of hepatic progenitor cells (HPCs) in the pathogenesis of liver fibrosis have been identified. Nevertheless, the precise mechanism underlying the role of HPCs in liver fibrosis in schistosomiasis remains unclear. This study examined how autophagy in HPCs affects schistosomiasis-induced liver fibrosis by modulating exosomal miRNAs. The activation of HPCs was verified by immunohistochemistry (IHC) and immunofluorescence (IF) staining in fibrotic liver from patients and mice with Schistosoma japonicum infection. By coculturing HPCs with hepatic stellate cells (HSCs) and assessing the autophagy level in HPCs by proteomic analysis and in vitro phenotypic assays, we found that impaired autophagy degradation in these activated HPCs was mediated by lysosomal dysfunction. Blocking autophagy by the autophagy inhibitor chloroquine (CQ) significantly diminished liver fibrosis and granuloma formation in S. japonicum-infected mice. HPC-secreted extracellular vehicles (EVs) were further isolated and studied by miRNA sequencing. miR-1306-3p, miR-493-3p, and miR-34a-5p were identified, and their distribution into EVs was inhibited due to impaired autophagy in HPCs, which contributed to suppressing HSC activation. In conclusion, we showed that the altered autophagy process upon HPC activation may prevent liver fibrosis by modulating exosomal miRNA release and inhibiting HSC activation in schistosomiasis. Targeting the autophagy degradation process may be a therapeutic strategy for liver fibrosis during Schistosoma infection.
The biodegradation of antibiotics in aquatic environment is consistently impeded by the widespread presence of heavy metals, necessitating urgent measures to mitigate or eliminate this environmental stress. This work investigated the degradation of sulfamethoxazole (SMX) by the white-rot fungus Phanerochaete chrysosporium (WRF) under heavy metal cadmium ion (Cd2+) stress, with a focus on the protective effects of reduced graphene oxide (RGO). The pseudo-first-order rate constant and removal efficiency of 5 mg/L SMX in 48 h by WRF decrease from 0.208 h-1 and 55.6% to 0.08 h-1 and 28.6% at 16 mg/L of Cd2+, while these values recover to 0.297 h-1 and 72.8% by supplementing RGO. The results demonstrate that RGO, possessing excellent biocompatibility, effectively safeguard the mycelial structure of WRF against Cd2+ stress and provide protection against oxidative damage to WRF. Simultaneously, the production of manganese peroxidase (MnP) by WRF decreases to 38.285 U/L in the presence of 24 mg/L Cd2+, whereas it recovers to 328.51 U/L upon the supplement of RGO. RGO can induce oxidative stress in WRF, thereby stimulating the secretion of laccase (Lac) and MnP to enhance the SMX degradation. The mechanism discovered in this study provides a new strategy to mitigate heavy metal stress encountered by WRF during antibiotic degradation.
Biodegradation, Environmental , Cadmium , Graphite , Phanerochaete , Sulfamethoxazole , Phanerochaete/metabolism , Sulfamethoxazole/metabolism , Cadmium/metabolism , Water Pollutants, Chemical/metabolism
INTRODUCTION: This study aimed to investigate the effects of nicotine on the activation of pancreatic stellate cells (PSCs) and pancreatic fibrosis in chronic pancreatitis (CP), along with its underlying molecular mechanisms. METHODS: This was an in vivo and in vitro study. In vitro, PSCs were cultured to study the effects of nicotine on their activation and oxidative stress. Transcriptome sequencing was performed to identify potential signaling pathways involved in nicotine action. And the impact of nicotine on mitochondrial Ca2+ levels and Ca2+ transport-related proteins in PSCs was analyzed. The changes in nicotine effects were observed after the knockdown of the mitochondrial calcium uniporter (MCU) in PSCs. In vivo experiments were conducted using a mouse model of CP to assess the effects of nicotine on pancreatic fibrosis and oxidative stress in mice. The alterations in nicotine effects were observed after treatment with the MCU inhibitor Ru360. RESULTS: In vitro experiments demonstrated that nicotine promoted PSCs activation, characterized by increased cell proliferation, elevated α-SMA and collagen expression. Nicotine also increased the production of reactive oxygen species (ROS) and cellular malondialdehyde (MDA), exacerbating oxidative stress damage. Transcriptome sequencing revealed that nicotine may exert its effects through the calcium signaling pathway, and it was verified that nicotine elevated mitochondrial Ca2+ levels and upregulated MCU expression. Knockdown of MCU reversed the effects of nicotine on mitochondrial calcium homeostasis, improved mitochondrial oxidative stress damage and structural dysfunction, thereby alleviating the activation of PSCs. In vivo validation experiments showed that nicotine significantly aggravated pancreatic fibrosis in CP mice, promoted PSCs activation, exacerbated pancreatic tissue oxidative stress, and increased MCU expression. However, treatment with Ru360 significantly mitigated these effects. CONCLUSIONS: This study confirms that nicotine upregulates the expression of MCU, leading to mitochondrial calcium overload and exacerbating oxidative stress in PSCs, and ultimately promoting PSCs activation and exacerbating pancreatic fibrosis in CP.
The retinal microcirculation system constitutes a unique terminal vessel bed of the systemic circulation, and its perfusion status is directly associated with the neural function of the retina. This vascular network, essential for nourishing various layers of the retina, comprises two primary microcirculation systems: the retinal microcirculation and the choroidal microcirculation, with each system supplying blood to distinct retinal layers and maintaining the associated neural function. The blood flow of those capillaries is regulated via different mechanisms. However, a range of internal and external factors can disrupt the normal architecture and blood flow within the retinal microcirculation, leading to several retinal pathologies, including diabetic retinopathy, macular edema, and vascular occlusions. Metabolic disturbances such as hyperglycemia, hypertension, and dyslipidemia are known to modify retinal microcirculation through various pathways. These alterations are observable in chronic metabolic conditions like diabetes, coronary artery disease, and cerebral microvascular disease due to advances in non-invasive or minimally invasive retinal imaging techniques. Thus, examination of the retinal microcirculation can provide insights into the progression of numerous chronic metabolic disorders. This review discusses the anatomy, physiology and pathophysiology of the retinal microvascular system, with a particular emphasis on the connections between retinal microcirculation and systemic circulation in both healthy states and in the context of prevalent chronic metabolic diseases.
Metabolic Diseases , Microcirculation , Retinal Vessels , Humans , Microcirculation/physiology , Retinal Vessels/physiopathology , Metabolic Diseases/physiopathology , Retinal Diseases/physiopathology , Regional Blood Flow/physiology
Chemoselective extraction strategy is an emerging and powerful means for targeted metabolomics analysis, which allows for the selective identification of biomarkers. Short-chain fatty acids (SCFAs) as functional metabolites for many diseases pose challenges in qualitative and quantitative analyses due to their high polarity and uneven abundance. In our study, we proposed the B-labeled method for the derivatization of SCFAs using easily available 3-aminobenzeneboronic acid as the derivatization reagent, which enables the introduction of recognition unit (boric acid groups). To analyze the B-labeled targeted metabolites accurately, cis-diol-based covalent organic framework (COF) was designed to specifically capture and release target compounds by pH-response borate affinity principle. The COF synthesized by the one-step Schiff base reaction possessed a large surface area (215.77 m2/g), excellent adsorption capacity (774.9 µmol/g), good selectivity, and strong regeneration ability (20 times). Combined with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis, our results indicated that the detection sensitivities of SCFAs increased by 1.2-2500 folds compared with unlabeled method, and the retention time and isomer separation were improved. Using this strategy, we determined twenty-six SCFAs in the serum and urine of rats in four groups about osteoporosis and identified important biomarkers related to the tricarboxylic acid cycle and fatty acid metabolism pathways. In summary, UHPLC-MS/MS based on B-labeled derivatization with tailored COF strategy shows its high selectivity, excellent sensitivity, and good chromatographic behavior and has remarkable application prospect in targeted metabolomics study of biospecimens.
Fatty Acids, Volatile , Metabolomics , Tandem Mass Spectrometry , Animals , Chromatography, High Pressure Liquid , Tandem Mass Spectrometry/methods , Fatty Acids, Volatile/analysis , Fatty Acids, Volatile/metabolism , Metabolomics/methods , Rats , Metal-Organic Frameworks/chemistry , Rats, Sprague-Dawley , Male , Boronic Acids/chemistry
BACKGROUND: The emergence of drug-resistant strains of Klebsiella pneumoniae (K. pneumoniae) has become a significant challenge in the field of infectious diseases, posing an urgent need for the development of highly protective vaccines against this pathogen. METHODS AND RESULTS: In this study, we identified three immunogenic extracellular loops based on the structure of five candidate antigens using sera from K. pneumoniae infected mice. The sequences of these loops were linked to the C-terminal of an alpha-hemolysin mutant (mHla) from Staphylococcus aureus to generate a heptamer, termed mHla-EpiVac. In vivo studies confirmed that fusion with mHla significantly augmented the immunogenicity of EpiVac, and it elicited both humoral and cellular immune responses in mice, which could be further enhanced by formulation with aluminum adjuvant. Furthermore, immunization with mHla-EpiVac demonstrated enhanced protective efficacy against K. pneumoniae channeling compared to EpiVac alone, resulting in reduced bacterial burden, secretion of inflammatory factors, histopathology and lung injury. Moreover, mHla fusion facilitated antigen uptake by mouse bone marrow-derived cells (BMDCs) and provided sustained activation of these cells. CONCLUSIONS: These findings suggest that mHla-EpiVac is a promising vaccine candidate against K. pneumoniae, and further validate the potential of mHla as a versatile carrier protein and adjuvant for antigen design.
Bacterial Vaccines , Epitopes , Klebsiella Infections , Klebsiella pneumoniae , Animals , Klebsiella pneumoniae/immunology , Klebsiella Infections/prevention & control , Klebsiella Infections/immunology , Klebsiella Infections/microbiology , Bacterial Vaccines/immunology , Bacterial Vaccines/administration & dosage , Mice , Female , Epitopes/immunology , Mice, Inbred BALB C , Antigens, Bacterial/immunology , Lung/microbiology , Lung/immunology , Lung/pathology , Immunity, Cellular/drug effects , Staphylococcus aureus/immunology , Adjuvants, Immunologic/pharmacology , Immunity, Humoral/drug effects
Solution pH is one of the primary factors affecting the efficiency of water decontamination. Although the influence of pH on oxidants activation, catalyst activity, and reactive oxygen species have been widely explored, there is still a scarcity of systemic studies on the changes in the oxidation behavior of organic pollutants at different pH levels. Herein, we report the influence laws of pH on the forms, reactivities, active sites, degradation pathways, and products toxicities of organic pollutants. Changes in pH cause the protonation or deprotonation of organic pollutants and further affect their forms and chemistry (e.g., electrostatic force, hydrophobicity, and oxidation potential). The oxidation potential of organic pollutants follows the order: protonated form > pristine form > deprotonated form. Moreover, protonation or deprotonation can modify the active sites and degradation pathways of organic pollutants, wherein deprotonation renders them more susceptible to electrophilic attack, while protonation reduces their activity against electrophilic and nucleophilic attacks. Additionally, pH adjustments can modify the degradation pathway and the toxicity of transformation products. Overall, pH changes can affect the oxidation fate of organic pollutants by altering their structure, which distinguishes it from the effect of pH on oxidants or oxidant activation processes.
Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.
Cholestasis , Hepatocytes , Animals , Mice , Cholestasis/genetics , Cholestasis/pathology , Cholestasis/metabolism , Hepatocytes/metabolism , Liver/metabolism , Liver/injuries , Liver/pathology , Cell Proliferation/genetics , Bile Ducts/metabolism , Liver Regeneration/genetics , Mice, Inbred C57BL , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Signal Transduction , Male , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/genetics , Transcriptome , Disease Models, Animal , Spatio-Temporal Analysis
The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/ß-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.
Homeostasis , Liver Regeneration , Liver , Wnt Signaling Pathway , Animals , Liver Regeneration/genetics , Mice , Liver/metabolism , Wnt Signaling Pathway/genetics , Hepatocytes/metabolism , Hepatocytes/cytology , Cell Proliferation/genetics , Single-Cell Analysis , Gene Regulatory Networks , Gene Expression Profiling/methods , Transcriptome , Mice, Inbred C57BL , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Male
Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.
Aging , Muscle, Skeletal , Single-Cell Analysis , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Aging/genetics , Aging/pathology , Aging/physiology , Cell Nucleus/metabolism , Chromatin/metabolism , Chromatin/genetics , Disease Susceptibility , Epigenesis, Genetic , Frailty/genetics , Frailty/pathology , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Sarcopenia/genetics , Sarcopenia/pathology , Transcriptome
BACKGROUND: Previous studies have indicated the potential occurrence of alexithymia among stroke patients, yet the prevalence of alexithymia in this population remains disparate across different investigations without a synthesized overview. AIM: To systematically evaluate the prevalence and characteristics of alexithymia in stroke patients. METHODS: A systematic review and meta-analysis was conducted following the PRISMA guidelines. PubMed, Embase, Web of Science, The Cochrane Library, CINAHL, China Knowledge Resource Integrated Database (CNKI), Wanfang Database, Chinese Biomedical Database, and Weipu Database (VIP) were searched from inception to December 31,2022, two independent researchers extracted data and evaluated article quality. RESULTS: Seventeen studies were included, reporting on the prevalence of alexithymia or Toronto Alexithymia Scale-20 (TAS-20) scores among stroke patients. The pooled prevalence was found to be 35.0% (95%CI= 23.0-47.0%; I2 =97.5%), and the total scores (TS) of TAS-20 was 59.90 (95% CI=56.34-63.47; I2 =100.0%). Subgroup analysis revealed significant variation in TAS-20 scores across different geographical regions. Specifically, the total TAS-20 score in Chinese stroke patients (62.95, 95%CI=58.75-67.14; I2=100%) was higher compared to non-Chinese stroke patients (52.58, 95%CI=49.12-56.04; I2 = 99.0%). CONCLUSIONS: The prevalence of alexithymia is high among stroke patients, with TAS-20 scores surpassing those observed in patients with certain other medical conditions. This underscores the importance of addressing alexithymia in stroke patients promptly through assessment and intervention to mitigate negative emotional consequences and enhance overall quality of life. Future research could explore the influence of demographic factors such as age and sex on alexithymia in stroke patients, enabling a more comprehensive understanding of alexithymia.
