Higher-Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling.

Receptor clustering on the cell membrane is critical in the signaling of many immunoreceptors, and this mechanism has previously been attributed to the extracellular and/or the intracellular interactions. Here, we report an unexpected finding that for death receptor 5 (DR5), a receptor in the tumor necrosis factor receptor superfamily, the transmembrane helix (TMH) alone in the receptor directly assembles a higher-order structure to drive signaling and that this structure is inhibited by the unliganded ectodomain. Nuclear magnetic resonance structure of the TMH in bicelles shows distinct trimerization and dimerization faces, allowing formation of dimer-trimer interaction networks. Single-TMH mutations that disrupt either trimerization or dimerization abolish ligand-induced receptor activation. Surprisingly, proteolytic removal of the DR5 ectodomain can fully activate downstream signaling in the absence of ligand. Our data suggest a receptor activation mechanism in which binding of ligand or antibodies to overcome the pre-ligand autoinhibition allows TMH clustering and thus signaling.

DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).

In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,ß-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.

Dual chemical labeling enables nucleotide-resolution mapping of DNA abasic sites and common alkylation damage in human mitochondrial DNA.

Mitochondrial DNA (mtDNA) modifications play an emerging role in innate immunity and inflammatory diseases. Nonetheless, relatively little is known regarding the locations of mtDNA modifications. Such information is critically important for deciphering their roles in mtDNA instability, mtDNA-mediated immune and inflammatory responses, and mitochondrial disorders. The affinity probe-based enrichment of lesion-containing DNA represents a key strategy for sequencing DNA modifications. Existing methods are limited in the enrichment specificity of abasic (AP) sites, a prevalent DNA modification and repair intermediate. Herein, we devise a novel approach, termed dual chemical labeling-assisted sequencing (DCL-seq), for mapping AP sites. DCL-seq features two designer compounds for enriching and mapping AP sites specifically at single-nucleotide resolution. For proof of principle, we mapped AP sites in mtDNA from HeLa cells under different biological conditions. The resulting AP site maps coincide with mtDNA regions with low TFAM (mitochondrial transcription factor A) coverage and with potential G-quadruplex-forming sequences. In addition, we demonstrated the broader applicability of the method in sequencing other DNA modifications in mtDNA, such as N7-methyl-2'-deoxyguanosine and N3-methyl-2'-deoxyadenosine, when coupled with a lesion-specific repair enzyme. Together, DCL-seq holds the promise to sequence multiple DNA modifications in various biological samples.

Consistency Analysis of Programmed Death Ligand 1 Expression in Non-Small Cell Lung Cancer Between Pleural Effusion and Matched Primary Lung Cancer Tissues by Immunohistochemical Double Staining.

In clinical practice, programmed death ligand 1 (PD-L1) detection is prone to nonspecific staining due to the complex cellular composition of pleural effusion smears. In this study, diaminobenzidine (DAB) and 3-amino-9-ethylcarbazole (AEC) immunohistochemistry double staining was performed to investigate PD-L1 expression in tumor cells from malignant pleural effusion (MPE). MPE was considered as a metastasis in non-small cell lung cancer patients; thus, the heterogeneity between metastatic and primary lung cancer was revealed as well. Ninety paired specimens of MPE cell blocks and matched primary lung cancer tissues from non-small cell lung cancer patients were subjected to PD-L1 and thyroid transcription factor-1(TTF-1)/p63 immunohistochemistry double staining. Two experienced pathologists independently evaluated PD-L1 expression using 3 cutoffs (1%, 10%, and 50%). PD-L1 expression in MPE was strongly correlated with that in matched primary lung cancer tissues (R = 0.813; P < .001). Using a 4-tier scale (cutoffs: 1%, 10%, and 50%), the concordance was 71.1% (Cohen's κ = .534). Using a 2-tier scale, the concordance was 75.6% (1%, Cohen's κ = 0.53), 78.9% (10%, Cohen's κ = 0.574), and 95.6% (50%, Cohen's κ = 0.754). The rates of PD-L1 positivity in MPE (56.7%) were higher than that in lung tissues (32.2%). All 27 discordant cases had higher scores in MPE. The double-staining method provided superior identification of PD-L1-positive tumor cells on a background with nonspecific staining. In conclusion, PD-L1 expression was moderately concordant between metastatic MPE cell blocks and matched primary lung carcinoma tissues, with variability related to tumor heterogeneity. MPE should be considered to detect PD-L1 when histological specimens are unattainable, especially when PD-L1 expression is >50%. PD-L1 positivity rates were higher in MPE. Double staining can improve PD-L1 detection by reducing false-negative/positive results.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

Liquid-based cytology specimens for next-generation sequencing in lung adenocarcinoma: challenges and evaluation of targeted therapy.

BACKGROUND: To explore challenges of liquid-based cytology (LBC) specimens for next-generation sequencing (NGS) in lung adenocarcinoma and evaluate the efficacy of targeted therapy. METHODS: A retrospective analysis was conducted on the NGS test of 357 cases of advanced lung adenocarcinoma LBC specimens and compared with results of histological specimens to assess the consistency. The impact of tumor cellularity on NGS test results was evaluated. The utility of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) was collected. Clinical efficacy evaluation was performed and survival curve analysis was conducted using the Kaplan-Meier method. RESULTS: There were 275 TKI-naive and 82 TKI-treated specimens, the mutation rates of cancer-related genes detected in both groups were similar (86.2% vs. 86.6%). The EGFR mutation rate in the TKI treated group was higher than that in the TKI-naive group (69.5% > 54.9%, P = 0.019). There was no significant difference in the EGFR mutation frequency among different tumor cellularity in the TKI-naive group. However, in the TKI treated group, the frequency of EGFR sensitizing mutation and T790M resistance mutation in specimens with < 20% tumor cellularity was significantly lower than that in specimens with ≥ 20% tumor cellularity. Among 22 cases with matched histological specimens, 72.7% (16/22) of LBC specimens were completely consistent with results of histological specimens. Among 92 patients with EGFR-mutant lung adenocarcinoma treated with EGFR-TKIs in the two cohorts, 88 cases experienced progression, and the median progression-free survival (PFS) was 12.1 months. CONCLUSIONS: Cytological specimens are important sources for gene detection of advanced lung adenocarcinoma. When using LBC specimens for molecular testing, it is recommended to fully evaluate the tumor cellularity of the specimens.

Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells.

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.

Association between social capital and utilization of essential public health services among elderly migrants: a multilevel logistic study based on the 2017 China migrant dynamic survey (CMDS).

BACKGROUND: As the number of elderly migrants in China continues to grow, it is necessary to pay closer attention to their health and health services. Some studies have confirmed that social capital plays a significant role in the utilization of health services. Therefore, an in-depth exploration of the relationship between social capital and the utilization of essential public health services (EPHS) by elderly migrants will not only contribute to improving their overall health but also facilitate a more balanced development of public health service system in China. METHODS: Based on the cross-sectional data from the 2017 China Migrants Dynamic Survey (CMDS), this study examined the impact of social capital on the utilization of EPHS among elderly migrants. We evaluated social capital at two distinct levels: the individual and the community, and considered two dimensions of social capital: structural social capital (SSC) and cognitive social capital (CSC). The study aimed to delve into the impact of these forms of social capital on the utilization of EPHS among elderly migrants, and whether the migration range moderates this impact by multilevel logistic regression analysis. RESULTS: A total of 5,728 migrant elderly individuals were selected. The health records establishment rate and health education acceptance rate were approximately 33.0% and 58.6%, respectively. Social capital influenceed the utilization of EPHS among elderly migrants. Specifically, individual-level SSC and CSC have impacts on both the establishment of health records (OR = 1.598, 95%CI 1.366-1.869; OR = 1.705, 95%CI 1.433-2.028) and the acceptance of health education (OR = 1.345, 95%CI 1.154-1.567; OR = 2.297, 95%CI 1.906-2.768) among elderly migrants, while community-level SSC only affected the acceptance of health education (OR = 3.838, 95%CI 1.328-11.097). There were significant differences in individual-level SSC, health records, and health education among different migration range subgroups among elderly migrants. Migration range moderated the effect of social capital on the utilization of EPHS, crossing provinces could weaken the relationship between SSC and health education. CONCLUSIONS: Social capital is associated with a higher utilization rate of EPHS among elderly migrants. It is necessary to encourage them to actively participate in social activities, strengthen public services and infrastructure construction in the area, and improve their sense of belonging and identity.

Anesthetic Management of One-Lung Ventilation in Patients With Tracheal Bronchus: A Narrative Review.

Tracheal bronchus is a rare congenital tracheal abnormality that generally refers to the right upper lobe bronchus of the lung that originates from the trachea. Tracheal bronchus is usually asymptomatic and is often accidentally detected by fiberoptic bronchoscopy or computed tomography for other conditions. Depending on the location of the tracheal bronchial opening and possible anatomical variations, the management of 1-lung ventilation in patients with tracheal bronchus is a significant challenge for anesthesiologists. To provide a reference for anesthesiologists to better manage anesthesia in such patients, we review the pathophysiology, definition, and Conacher classification of tracheal bronchus and then discuss the diagnosis of tracheal bronchus and management of 1-lung ventilation during anesthesia according to the Conacher classification.

VLM catecholaminergic neurons control tumor growth by regulating CD8+ T cells.

It is known that tumor growth can be influenced by the nervous system. It is not known, however, if tumors communicate directly with the central nervous system (CNS) or if such interactions may impact tumor growth. Here, we report that ventrolateral medulla (VLM) catecholaminergic (CA) neurons in the mouse brain are activated in tumor-bearing mice and the activity of these neurons significantly alter tumor growth in multiple syngeneic and spontaneous mouse tumor models. Specific ablation of VLM CA neurons by a dopamine-ß-hydroxylase (DBH) promotor-activated apoptosis-promoting caspase-3 in Dbh-Cre mice as well as inhibition of these neurons by a chemogenetic method slowed tumor progression. Consistently, chemogenetic activation of VLM CA neurons promoted tumor growth. The tumor inhibition effect of VLM CA neuron ablation is mitigated in Dbh-Cre;Rag1-/- mice, indicating that this regulatory effect is mediated by the adaptive immune system. Specific depletion of CD8+ T cells using an anti-CD8+ antibody also mitigated the tumor suppression resulting from the VLM CA neuron ablation. Finally, we showed that the VLM CA neuronal ablation had an additive antitumor effect with paclitaxel treatment. Collectively, our study uncovered the role of VLM CA neurons in the mouse brain in controlling tumor growth in the mouse body.

Tissue damage, antioxidant capacity, transcriptional and metabolic regulation of red drum Sciaenops ocellatus in response to nanoplastics exposure and subsequent recovery.

Nanoplastics are recognized as emerging contaminants that can cause severe toxicity to marine fishes. However, limited researches were focusing on the toxic effects of nanoplastics on marine fish, especially the post-exposure resilience. In this study, red drum (Sciaenops ocellatus) were exposed to 5 mg/L polystyrene nanoplastics (100 nm, PS-NPs) for a 7-day exposure experiment, and a 14-day recovery experiment that followed. The aim was to evaluate the dynamic alterations in hepatic and branchial tissue damage, hepatic antioxidant capacity, as well as hepatic transcriptional and metabolic regulation in the red drum during exposure and post-exposure to PS-NPs. Histopathological observation found that PS-NPs primarily triggered hepatic lipid droplets and branchial epithelial liftings, a phenomenon persistently discernible up to the 14 days of recovery. Although antioxidant capacity partially recovered during recovery periods, PS-NPs resulted in a sustained reduction in hepatic antioxidant activity, causing oxidative damage throughout the entire exposure and recovery phases, as evidenced by decreased total superoxide dismutase activities and increased malondialdehyde content. At the transcriptional and metabolic level, PS-NPs primarily induced lipid metabolism disorders, DNA damage, biofilm disruption, and mitochondrial dysfunction. In the gene-metabolite correlation interaction network, numerous CcO (cytochrome c oxidase) family genes and lipid metabolites were identified as key regulatory genes and metabolites in detoxification processes. Among them, the red drum possesses one additional CcO6B in comparison to human and zebrafish, which potentially contributes to its enhanced capacity for maintaining a stable and positive regulatory function in detoxification. This study revealed that nanoplastics cause severe biotoxicity to red drum, which may be detrimental to the survival of wild populations and affect the economics of farmed populations.

Correlation between obesity and early vascular aging in middle-aged and young adult health check-up populations. / ä¸­é’å¹´å¥åº·ä½“æ£€äººç¾¤è‚¥èƒ–ä¸Žæ—©å‘è¡€ç®¡è€åŒ–çš„ç›¸å ³æ€§.

OBJECTIVES: The obesity rate among middle-aged and young adults in China is increasing annually, and the incidence of cardiovascular diseases is becoming more prevalent in younger populations. However, it has not yet been reported whether obesity is associated with early vascular aging (EVA). This study aims to explore the correlation between obesity and EVA in middle-aged and young adult health check-up populations, providing a reference for the prevention of cardiovascular diseases. METHODS: A total of 15 464 middle-aged and young adults aged 18-59 who completed brachial-ankle pulse wave velocity (baPWV) test in the Third Xiangya Hospital of Central South University from January to December 2020 were included. Among them, 1 965 individuals with normal blood pressure and no cardiovascular risk factors were selected as the healthy population. The baPWV thresholds for determining EVA in each age group for males and females were calculated based on the baPWV values of the healthy population. The number and percentage of individuals meeting the EVA criteria in the middle-aged and young adult health check-up populations were statistically analyzed by age and gender. The differences in obesity indicators [visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC)] between the EVA and non-EVA groups for males and females were compared. Using EVA as the dependent variable, VAI, BMI, and WC were included as independent variables in a Logistic model to analyze the correlation between each obesity indicator and EVA before and after adjusting for other influencing factors. Furthermore, the correlation between each obesity indicator and EVA in each age group was analyzed. RESULTS: In the health check-up populations, the detection rate of EVA in different age groups was 1.65%-10.92% for males, and 1.16%-10.50% for females, the detection rate of EVA increased with age in both males and females. Except for the 40-<50 age group, the EVA detection rate was higher in males than in females in all other age groups. Regardless of gender, obesity indicators VAI, BMI, and WC were significantly higher in the EVA group than in the non-EVA group (all P<0.01). Before and after adjusting for other influencing factors, VAI and WC were both correlated with EVA (both P<0.05). BMI was a risk factor for EVA before adjusting for other influencing factors (P<0.01), but after adjustment, the correlation between BMI and EVA was not statistically significant (P=0.05). After adjusting for other influencing factors, the correlation between VAI and EVA was statistically significant in the 18-<40 and 50-<60 age groups (both P<0.05), while the correlation between BMI and WC with EVA was not statistically significant (both P>0.05). In the 40-<50 age group, the correlation between VAI and BMI with EVA was not statistically significant (both P>0.05), but the correlation between WC and EVA was statistically significant (P<0.01). CONCLUSIONS: VAI is closely related to the occurrence of EVA in middle-aged and young adults aged 18-<40 and 50-<60 years, while WC is closely related to the occurrence of EVA in those aged 40-<50 years.

PANDORA-Seq unveils the hidden small noncoding RNA landscape in atherosclerosis of LDL receptor-deficient mice.

Small noncoding RNAs (sncRNAs) play diverse roles in numerous biological processes. While the widely used RNA sequencing (RNA-Seq) method has advanced sncRNA discovery, RNA modifications can interfere with the complementary DNA library construction process, preventing the discovery of highly modified sncRNAs including transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs) that may have important functions in disease development. To address this technical obstacle, we recently developed a novel PANDORA-Seq (Panoramic RNA Display by Overcoming RNA Modification Aborted Sequencing) method to overcome RNA modification-elicited sequence interferences. To identify novel sncRNAs associated with atherosclerosis development, LDL receptor-deficient (LDLR-/-) mice were fed a low-cholesterol diet or high-cholesterol diet (HCD) for 9 weeks. Total RNAs isolated from the intima were subjected to PANDORA-Seq and traditional RNA-Seq. By overcoming RNA modification-elicited limitations, PANDORA-Seq unveiled an rsRNA/tsRNA-enriched sncRNA landscape in the atherosclerotic intima of LDLR-/- mice, which was strikingly different from that detected by traditional RNA-Seq. While microRNAs were the dominant sncRNAs detected by traditional RNA-Seq, PANDORA-Seq substantially increased the reads of rsRNAs and tsRNAs. PANDORA-Seq also detected 1,383 differentially expressed sncRNAs induced by HCD feeding, including 1,160 rsRNAs and 195 tsRNAs. One of HCD-induced intimal tsRNAs, tsRNA-Arg-CCG, may contribute to atherosclerosis development by regulating the proatherogenic gene expression in endothelial cells. Overall, PANDORA-Seq revealed a hidden rsRNA and tsRNA population associated with atherosclerosis development. These understudied tsRNAs and rsRNAs, which are much more abundant than microRNAs in the atherosclerotic intima of LDLR-/- mice, warrant further investigations.

The 5'-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1).

In higher eukaryotes, mitochondria play multiple roles in energy production, signaling, and biosynthesis. Mitochondria possess multiple copies of mitochondrial DNA (mtDNA), which encodes 37 genes that are essential for mitochondrial and cellular function. When mtDNA is challenged by endogenous and exogenous factors, mtDNA undergoes repair, degradation, and compensatory synthesis. mtDNA degradation is an emerging pathway in mtDNA damage response and maintenance. A key factor involved is the human mitochondrial genome maintenance exonuclease 1 (MGME1). Despite previous biochemical and functional studies, controversies exist regarding the polarity of MGME1-mediated DNA cleavage. Also, how DNA sequence may affect the activities of MGME1 remains elusive. Such information is not only fundamental to the understanding of MGME1 but critical for deciphering the mechanism of mtDNA degradation. Herein, we use quantitative assays to examine the effects of substrate structure and sequence on the DNA-binding and enzymatic activities of MGME1. We demonstrate that MGME1 binds to and cleaves from the 5'-end of single-stranded DNA substrates, especially in the presence of 5'-phosphate, which plays an important role in DNA binding and optimal cleavage by MGME1. In addition, MGME1 tolerates certain modifications at the terminal end, such as a 5'-deoxyribosephosphate intermediate formed in base excision repair. We show that MGME1 processes different sequences with varying efficiencies, with dT and dC sequences being the most and least efficiently digested, respectively. Our results provide insights into the enzymatic properties of MGME1 and a rationale for the coordination of MGME1 with the 3'-5' exonuclease activity of DNA polymerase γ in mtDNA degradation.

Schemes for enhanced antioxidant stability in frying meat: a review of frying process using single oil and blended oils.

Deep-fried meat products are widely popular. However, harmful compounds produced by various chemical reactions during frying have been shown to be detrimental to human health. It is of great necessity to raise practical suggestions for improving the oxidation problem of frying oils and frying conditions in some aspects. Vegetable oils are not as thermally stable as saturated fats, and blended oils have higher thermal stability than single oil. In this review, we discussed the oxidation problems frying oils and meats are subject to during frying, starting from the oil oxidation mechanism, the effects of different oils and fats on the quality of different fried meats under different conditions were concluded to alleviate the oxidation problem, to highlight the necessity of applying blended oils for frying, and effective antioxidants added to frying oils are also introduced, that would provide more convenient and practical options for obtaining higher quality of fried meat products and offer better understanding of the potential of blended frying oils for frying meat products.

Application of carbon dots in food preservation: a critical review for packaging enhancers and food preservatives.

Carbon dots (CDs) have two unique advantages: one is ease of synthesis at low price, the other is desirable physical and chemical properties, such as ultra-small size, abundant surface functional groups, nontoxic/low-toxicity, good biocompatibility, excellent antibacterial and antioxidant activities etc. These advantages provide opportunities for the development of new food packaging enhancers and food preservatives. This paper systematically reviews the studies of CDs used to strengthen the physical properties of food packaging, including strengthen mechanical strength, ultraviolet (UV) barrier properties and water barrier properties. It also reviews the researches of CDs used to fabricate active packaging with antioxidant and/or antibacterial properties and intelligent packaging with the capacity of sensing the freshness of food. In addition, it analyzes the antioxidant and antibacterial properties of CDs as preservatives, and discusses the effect of CDs applied as coating agents and nano-level food additives for extension the shelf life of food samples. It also provides a brief review on the security and the release behavior of CDs.

Collect and analyze the effect of CDs on enhancing the physical properties of protective food packaging.Discuss the active of CDs and their application in active intelligent packaging.Analyze the application of CDs as coating agent and nano-level food additives.Discuss the security of CDs, including toxicity and the release behavior.

Expression analysis, clinical significance and potential function of PLXNB2 in acute myeloid leukaemia.

BACKGROUND: The overall survival (OS) rate of adult patients suffering from acute myeloid leukaemia (AML) remains unsatisfactory at less than 40%. Current risk stratification systems fail to provide accurate guidelines for precise treatment. Novel biomarkers for predicting prognosis are urgently needed. Plexin B2 (PLXNB2), a functional receptor of angiogenin (ANG), has been found to be aberrantly expressed in multitudinous tumours. We detected overexpression of PLXNB2 mRNA in AML via transcriptome microarray analysis. This study aims to explore the potential role of PLXNB2 as a biomarker of prognosis and a prospective target of AML. METHODS: qRT‒PCR was conducted to verify the expression of PLXNB2 mRNA in bone marrow mononuclear cells from AML patients. Immunohistochemical and immunofluorescence staining were performed and confirmed increased expression of PLXNB2 protein in AML bone marrow tissues. Data on PLXNB2 expression, prognosis and clinical features were accessed from multiple bioinformatic databases, including The Cancer Genome Atlas (TCGA). Genes coexpressed and correlated with PLXNB2 were identified and analysed in the TCGA AML cohort. Metascape was applied for functional and pathway enrichment analysis of genes related to PLXNB2. Small molecular agents and traditional Chinese medicines potentially targeting genes related to PLXNB2 were screened via the Connectivity Map, TCMSP and HIT databases. RESULTS: PLXNB2 mRNA and protein levels are higher in AML samples than in normal controls. Overexpression of PLXNB2 is associated with worse OS in AML. Patients with high PLXNB2 expression might benefit more from haematopoietic stem cell transplantation (HSCT) (indicated by prolonged OS) than those with only chemotherapy treatment. Differentially expressed genes between the high and low PLXNB2 expression groups were overlapped with PLXNB2-coexpressed genes, and genes that overlapped were enriched in immune functions, endothelial cell regulation and cell interaction gene sets, indicating the potential function of PLXNB2 in AML. A total of 36 hub genes were identified from the differentially expressed genes, and MRC1, IL10, CD163 and CCL22 had significant prognostic value for AML. Analysis of the connectivity map and traditional agents revealed that honokiol, morphines, triptolide and paeoniflorin could be potential treatment regimens. CONCLUSIONS: The overexpression of PLXNB2 is an adverse prognostic factor in adult AML patients and could be used as a potential biomarker. PLXNB2 might exert an oncogenic role by modulating immune functions, endothelial cell functions and cell interactions. AML patients with high PLXNB2 expression could benefit more from HSCT.

Higher ratio of serum uric acid to serum creatinine (SUA/SCr) increases the risk of metabolic unhealthy phenotype.

BACKGROUND AND AIM: It is very important to understand which factors play roles in switching from a healthy to an unhealthy metabolism. It is unclear if SUA/SCr is an independent risk factor for metabolic unhealthy phenotype. We examined whether SUA/SCr is associated with an increased risk for metabolic unhealthy phenotype in the Chinese population. METHODS AND RESULTS: As many as 3158 subjects aged 25-75 years who had a metabolic healthy phenotype at baseline were included in the retrospective cohort study. They were assigned to four groups based on the quartile of SUA/SCr. We compared the demographic and clinical characteristics among the four groups. The correlation between SUA/SCr and the risk of metabolic unhealthy phenotype in the overall population and stratified by subgroups was examined by logistic regression analyses. Greater SUA/SCr values were correlated with greater BMI, systolic and diastolic BP, TC, TG, RBC, WBC, HB, ALT, SUA and eGFR. During the two-year follow-up, 632 of the study subjects (20.01%) developed new-onset metabolic unhealthy phenotype from the total of 3158 study subjects. A statistically significant increase in the rates of metabolic unhealthy phenotype was observed with increasing SUA/SCr levels within each group. After multivariate adjustment, the adjusted ORs and 95% CIs were 1.44 (1.03-2.00) and 2.11 (1.52-2.94) in the Q3 group and Q4 group, respectively. CONCLUSION: SUA/SCr was positively related to the risk of metabolic unhealthy phenotype in the Chinese subjects, suggesting the potential of SUA/SCr to serve as an independent risk predictor in the development of metabolic unhealthy phenotype.

The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.

mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.

A simple and easy non-derivatization gas chromatography-mass spectrometry method for simultaneous quantification of valproic acid, gabapentin, pregabalin, and vigabatrin in human plasma.

Immunoassays are currently not available in commercial kits for the quantification of valproic acid, vigabatrin, pregabalin, and gabapentin, which also cannot suffer the limitations of interferences of substances with similar structures. Chromatography is a good alternative to immunoassay. In this study, a simple and robust non-derivatization gas chromatography-mass spectrometry method for simultaneous determination of the above four drugs in human plasma was developed and validated for therapeutic drug monitoring purposes. This method employed benzoic acid as the internal standard with hydrochloric acid for plasma acidification and ACN for precipitate protein. The supernatant was directly injected into gas chromatography-mass spectrometry for analysis. Good linearity was obtained with linear correlation coefficients of the four analytes of 0.9988-0.9996. Extraction recoveries of valproic acid, vigabatrin, pregabalin, and gabapentin were respectively in the ranges of 91.3%-94.5%, 90.0%-90.9%, 90.0%-92.1%, and 88.0%-92.2% with the relative standard deviation values less than 12.6%. Intra- and inter-batch precision and accuracy, and stability assays were all acceptable. Taken together, the novel method developed in this study provided easy plasma pretreatment, good extraction yield, and high chromatographic resolution, which has been successfully validated through the quantification of valproic acid in the plasma of 46 patients with epilepsy.