ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a serious threat to public health, but its underlying mechanism remains poorly understood. In screening important genes using Gene Importance Calculator (GIC) we developed previously, ribosomal modification protein rimK-like family member A (RIMKLA) was predicted as one essential gene but its functions remained largely unknown. The current study determined the roles of RIMKLA in regulating glucose and lipid metabolism. RIMKLA expression was reduced in livers of human and mouse with NAFLD. Hepatic RIMKLA overexpression ameliorated steatosis and hyperglycemia in obese mice. Hepatocyte-specific RIMKLA knockout aggravated high-fat diet (HFD)-induced dysregulated glucose/lipid metabolism in mice. Mechanistically, RIMKLA is a new protein kinase that phosphorylates betaine-homocysteine S-methyltransferase 1 (BHMT1) at threonine 45 (Thr45) site. Upon phosphorylation at Thr45 and activation, BHMT1 eliminated homocysteine (Hcy) to inhibit the activity of transcription factor activator protein 1 (AP1) and its induction on fatty acid synthase (FASn) and cluster of differentiation 36 (CD36) gene transcriptions, concurrently repressing lipid synthesis and uptake in hepatocytes. Thr45 to alanine (T45A) mutation inactivated BHMT1 to abolish RIMKLA's repression on Hcy level, AP1 activity, FASn/CD36 expressions, and lipid deposition. BHMT1 overexpression rescued the dysregulated lipid metabolism in RIMKLA-deficient hepatocytes. In summary, RIMKLA is a novel protein kinase that phosphorylates BHMT1 at Thr45 to repress lipid synthesis and uptake. Under obese condition, inhibition of RIMKLA impairs BHMT1 activity to promote hepatic lipid deposition.
Subject(s)
Betaine-Homocysteine S-Methyltransferase , Lipid Metabolism , Non-alcoholic Fatty Liver Disease , Animals , Mice , Humans , Betaine-Homocysteine S-Methyltransferase/genetics , Betaine-Homocysteine S-Methyltransferase/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Lipid Metabolism/genetics , Diet, High-Fat/adverse effects , Hepatocytes/metabolism , Male , Mice, Knockout , Phosphorylation/geneticsABSTRACT
Broadening of signals from atoms at interfaces can often be a limiting factor in applying solution NMR to the structure determination of complexes. Common contributors to such problems include exchange between free and bound states and the increased molecular weight of complexes relative to the free components, but another cause that can be more difficult to deal with occurs when conformational dynamics within the interface takes place at an intermediate rate on the chemical shift timescale. In this work we show how a carefully chosen mutation in the protein HMG-D rescued such a situation, making possible high-resolution structure determination of its complex with a dA2 bulge DNA ligand designed to mimic a natural DNA bend, and thereby revealing a new spatial organization of the complex.
ABSTRACT
Accurate intracellular visualization of human telomerase RNA (hTR) is imperative for early diagnosis and treatment monitoring of hepatocellular carcinoma (HCC). While isothermal amplification-based DNA cascade strategies are promising, challenges persist in achieving great intake efficiency of detection probes within tumor cells and enhancing intracellular reaction efficiency. This study introduces a SA@Comb-HCR nanosystem, a highly effective approach for in situ hTR detection in HCC cells. Sodium alginate-coated liposomes ensures efficient nanoprobe delivery, which are then combined with proximity effect-inspired signal amplification. The coating of sodium alginate facilitates receptor-mediated endocytosis, prevents serum protein adhesion, and mitigates cationic liposome cytotoxicity. The designed Comb-like consolidated hairpin probe enhances the concentration of the local reactant, resulting in cascade amplification upon hTR activation. This technique achieves precision detection of intracellularly overexpressed hTR in HCC cells with a remarkable detection limit of 0.7 pM. This approach holds great promise for advancing targeted and sensitive early clinical diagnosis of HCC.
Subject(s)
Biosensing Techniques , Carcinoma, Hepatocellular , Liver Neoplasms , RNA , Telomerase , Humans , Telomerase/genetics , Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Biosensing Techniques/methods , RNA/chemistry , RNA/genetics , Cell Line, Tumor , Nucleic Acid Amplification Techniques/methods , Limit of Detection , Liposomes/chemistryABSTRACT
Millions of patients suffer from type 1 diabetes (T1D) and its associated complications. Nevertheless, the pursuit of a cure for T1D has encountered significant challenges, with a crucial impediment being the lack of biomarkers that can accurately predict the progression of T1D and reliable therapeutic targets for T1D. Hence, there is an urgent need to discover novel protein biomarkers and therapeutic targets, which holds promise for targeted therapy for T1D. In this study, we extracted summary-level data on 4907 plasma proteins from 35,559 Icelanders and 2923 plasma proteins from 54,219 UK participants as exposures. The genome-wide association study (GWAS) summary statistics on T1D and T1D with complications were obtained from the R9 release results from the FinnGen consortium. Summary-data-based Mendelian randomization (SMR) analysis was employed to evaluate the causal associations between the genetically predicted levels of plasma proteins and T1D-associated outcomes. Colocalization analysis was utilized to investigate the shared genetic variants between the exposure and outcome. Moreover, transcriptome analysis and a protein-protein interaction (PPI) network further illustrated the expression patterns of the identified protein targets and their interactions with the established targets of T1D. Finally, a Mendelian randomization phenome-wide association study evaluated the potential side effects of the identified core protein targets. In the primary SMR analysis, we identified 72 potential protein targets for T1D and its complications, and nine of them were considered crucial protein targets. Within the group were five risk targets and four protective targets. Backed by evidence from the colocalization analysis, the protein targets were classified into four tiers, with MANSC4, CTRB1, SIGLEC5 and MST1 being categorized as tier 1 targets. Delving into the DrugBank database, we retrieved 11 existing medications for T1D along with their therapeutic targets. The PPI network clarified the interactions among the identified potential protein targets and established ones. Finally, the Mendelian randomization phenome-wide association study corroborated MANSC4 as a reliable target capable of mitigating the risk of various forms of diabetes, and it revealed the absence of adverse effects linked to CTRB1, SIGLEC5 and MST1. This study unveiled many protein biomarkers and therapeutic targets for T1D and its complications. Such advancements hold great promise for the progression of drug development and targeted therapy for T1D.
ABSTRACT
BACKGROUND: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet ß cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed. METHODS: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays. RESULTS: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers. CONCLUSIONS: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.
Subject(s)
Adenosine Triphosphate , Connexins , Gluconeogenesis , Lipogenesis , Liver , Nerve Tissue Proteins , Animals , Connexins/metabolism , Mice , Gluconeogenesis/physiology , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Adenosine Triphosphate/metabolism , Lipogenesis/physiology , Liver/metabolism , Mice, Knockout , Male , Humans , Diet, High-Fat/adverse effects , CytokinesABSTRACT
Acquired pure red cell aplasia (PRCA) is anemia associated with the absence of erythroblasts and is characterized by persistent and easy recurrence. However, the underlying mechanisms of acquired PRCA remain obscure, and the role of gene mutations in the pathogenesis of acquired PRCA is not fully characterized. In the present study, we detected thirty newly diagnosed patients with acquired PRCA using whole exome sequencing, and a potential role for STK10 in acquired PRCA was uncovered. The mRNA levels of STK10 in three patients with STK10 mutations were decreased. These three patients had a poor response to immunosuppressive therapy and two died in the follow-up period. Here we report that knockdown of STK10 inhibits erythroid differentiation and promotes apoptosis of K562 cells. We show that knockdown of STK10 resulted in inhibition of ribosome biogenesis and reduced ribosome levels in K562 cells. We also show that the p53 signaling pathway is activated by knockdown of STK10. Our results imply that ribosome biogenesis downregulation together with pathological p53 activation prevents normal erythropoiesis. Our study uncovers a new pathophysiological mechanism leading to acquired PRCA driven by STK10 mutations.
Subject(s)
Erythropoiesis , Mutation , Protein Serine-Threonine Kinases , Red-Cell Aplasia, Pure , Ribosomes , Humans , Erythropoiesis/genetics , Red-Cell Aplasia, Pure/genetics , Protein Serine-Threonine Kinases/genetics , K562 Cells , Male , Female , Ribosomes/metabolism , Ribosomes/genetics , Middle Aged , Aged , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Apoptosis , Gene Knockdown Techniques , AdultABSTRACT
The effects of rare earth Ce on the microstructure and properties of cast pure copper were investigated through thermodynamic calculations, XRD analysis, mechanical testing, metallographic microscopy, and scanning electron microscopy (SEM). The experimental results demonstrate that the reaction between rare earth Ce and oxygen as well as sulfur in copper exhibits a significantly negative Gibbs free energy value, indicating a strong thermodynamic driving force for deoxidation and desulfurization reactions. Ce is capable of removing trace amounts of O and S from copper. Moreover, the maximum solid solubility of Ce in Cu falls within the range of 0.009% to 0.01%. Furthermore, Ce can refine columnar grains while enlarging equiaxed grains in as-cast copper. Upon the addition of rare earth Ce, the tensile strength increased by 8.45%, elongation increased by 12.1%, and microhardness rose from 73.5 HV to 81.2 HV-an increase of 10.5%. Overall, rare earth Ce has been found to enhance both the microstructure and mechanical properties of cast pure copper.
ABSTRACT
Non-metallic inclusions in steel have great influence on the continuity of the steel matrix and the mechanical properties of steel. The precipitation sequence of Ce inclusions in molten steel is predicted by thermodynamic calculations. The results show that Ce content will affect the precipitation sequence of rare earth inclusions in molten steel, and the formation of CeO2, Ce2O3 and CeAlO3 will be inhibited with the increase in Ce content. Our laboratory smelted the test steel without rare earth additive and the test steel with rare earth Ce additive (0.0008%, 0.0013%, 0.0032%, 0.0042%). It was found that the MnS inclusions and inclusions containing Al, Ca, Mg and Si oxides or sulfides in the steel after rare earth addition were modified into complex inclusions containing CeAlO3 and Ce2O2S. The size of inclusion in steel was reduced and the aspect ratio of inclusion was improved. The addition of Ce also improved the grain size of U75V steel and significantly refined the pearlite lamellar spacing. After mechanical property testing of the test steel, it was found that when Ce is increased within 0.0042%, the tensile and impact properties of U75V steel are also improved.
ABSTRACT
Mitochondrial protein sequence similarity 3 gene family member A (FAM3A) plays important roles in the electron transfer chain, while its functions in the heart are still unknown. This study aims to explore the roles and mechanisms of FAM3A after myocardial infarction (MI). FAM3A-deficient (Fam3a-/-) mice were implemented with MI injury and showed lower survival rates at 4 weeks as well as decreased cardiac systolic function. Isolated cardiomyocytes of Fam3a-/- mice showed reduced basal, ATP-linked respiration and respiratory reserve compared to that of wild-type mice. Transmission electron microscopy studies showed Fam3a-/- mice had a larger size and elevated density of mitochondria. FAM3A deficiency also induced elevated mitochondrial Ca2+, higher opening level of mPTP, lower mitochondrial membrane potential and elevated apoptotic rates. Further analyses demonstrated that mitochondrial dynamics protein Opa1 contributed to the effects of FAM3A in cardiomyocytes. Our study discloses the important roles of mitochondrial protein FAM3A in the heart.
Subject(s)
Heart Failure , Mitochondrial Diseases , Myocardial Infarction , Mice , Animals , Heart Failure/genetics , Heart Failure/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Mitochondrial Diseases/metabolism , Myocytes, Cardiac/metabolism , Cytokines/metabolismABSTRACT
Radiosensitization efficacy of conventional tumor radiosensitizers has been frequently limited by insufficient competence for tumor microenvironment (TME) regulation and unfavorable cellular uptake at biological barriers. Here, we reported an ultra-efficient radiotherapy (RT) strategy by synthesizing an extracellular vesicles (EVs)-encapsulated hollow MnO2 to load metformin (Met@HMnER). It demonstrated significant RT enhancement by morphological control of catalyst and cellular respiratory depression against conventional solid MnO2. Furthermore, the target-modified EVs clothing retains outstanding metformin loading capacity while endowing enhanced biological barrier penetration. A noticeably durable innate immune activation of NK cells was triggered with this nanoplatform via the cGAS-STING pathway. The enhanced immunocompetence was verified on distal metastasis and in-situ recurrence model in vivo, This work paved a new path for synergistic and robust innate immunity in clinical cancer treatment.
Subject(s)
Metformin , Neoplasms , Humans , Trained Immunity , Manganese Compounds , Tumor Microenvironment , Oxides , Hypoxia , Immunosuppressive Agents , Immunotherapy , Neoplasms/therapyABSTRACT
Cancer-derived small extracellular vesicles (csEVs) are crucial liquid biopsy indicators that reflect the presence and progression of many malignancies. However, reliable discrimination of csEVs remains a great challenge owing to the interference from normal sEVs (nsEVs) and low abundance in the early stages of cancer. In this work, we developed a Two-Elements Selectively Triggered csEVs Recognization (TESTER) strategy for selective identification of csEVs from the complex clinical body fluid samples. This method was based on the MNAzyme-controlled synchronous recognition to EpCAM and CD63 proteins on the membrane of csEVs. Efficient recognition to csEVs via EpCAM aptamer and CD63 aptamer prompted the release of Partzyme A and Partzyme B probes to induce a MNAzyme structure formation, resulting in the cyclic cleavage of substrate chain to produce cascade fluorescence signal amplification. The detection threshold of the developed TESTER approach for csEVs in complicated biological samples was 72 particles µL-1, accomplishing the highly sensitive and selective quantification of csEVs. At the same time, we successfully constructed a new platform for bimolecular simultaneous recognition, which provides a good idea for the construction of bimolecular-activated detection switch in the future.
ABSTRACT
BACKGROUND: Antepartum depression is a prevalent unhealthy mental health problem worldwide, particularly in low-income countries. It is a major contributor to adverse birth outcomes. Previous studies linking antepartum depression to birthweight have yielded conflicting results, which may be the reason that the depressive symptoms were only measured once during pregnancy. This study aimed to explore the associations between trajectories of antepartum depressive symptoms and birthweight. METHODS: Depressive symptoms were assessed prospectively at each trimester in 3699 pregnant women from 24 hospitals across 15 provinces in China, using the Edinburgh Postpartum Depression Scale (EPDS). Higher scores of EPDS indicated higher levels of depressive symptoms. Associations between trajectories of depressive symptoms and birthweight were examined using group-based trajectory modeling (GBTM), propensity score-based inverse probability of treatment weighting (IPTW), and logistic regression. RESULTS: GBTM identified five trajectories. Compared with the low-stable trajectory of depressive symptoms, only high-stable (OR = 1.35, 95% CI: 1.15-2.52) and moderate-rising (OR = 1.18, 95% CI: 1.12-1.85) had an increased risk of low birthweight (LBW) in the adjusted longitudinal analysis of IPTW. There was no significant increase in the risk of LBW in moderate-stable and high-falling trajectories. However, trajectories of depressive symptoms were not associated with the risk of macrosomia. CONCLUSION: Antepartum depressive symptoms were not constant. Trajectories of depressive symptoms were associated with the risk of LBW. It is important to optimize and implement screening, tracking, and intervention protocols for antepartum depression, especially for high-risk pregnant women, to prevent LBW.
Subject(s)
Depression, Postpartum , Pregnancy Complications , Female , Pregnancy , Humans , Depression/epidemiology , Depression/diagnosis , Birth Weight , Prospective Studies , Pregnant Women/psychology , Pregnancy Complications/psychology , Depression, Postpartum/diagnosis , Risk FactorsABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide; however, the underlying mechanisms remain poorly understood. FAM3D is a member of the FAM3 family; however, its role in hepatic glycolipid metabolism remains unknown. Serum FAM3D levels are positively correlated with fasting blood glucose levels in patients with diabetes. Hepatocytes express and secrete FAM3D, and its expression is increased in steatotic human and mouse livers. Hepatic FAM3D overexpression ameliorated hyperglycemia and steatosis in obese mice, whereas FAM3D-deficient mice exhibited exaggerated hyperglycemia and steatosis after high-fat diet (HFD)-feeding. In cultured hepatocytes, FAM3D overexpression or recombinant FAM3D protein (rFAM3D) treatment reduced gluconeogenesis and lipid deposition, which were blocked by anti-FAM3D antibodies or inhibition of its receptor, formyl peptide receptor 1 (FPR1). FPR1 overexpression suppressed gluconeogenesis and reduced lipid deposition in wild hepatocytes but not in FAM3D-deficient hepatocytes. The addition of rFAM3D restored FPR1's inhibitory effects on gluconeogenesis and lipid deposition in FAM3D-deficient hepatocytes. Hepatic FPR1 overexpression ameliorated hyperglycemia and steatosis in obese mice. RNA sequencing and DNA pull-down revealed that the FAM3D-FPR1 axis upregulated the expression of heterogeneous nuclear ribonucleoprotein U (hnRNP U), which recruits the glucocorticoid receptor (GR) to the promoter region of the short-chain acyl-CoA dehydrogenase (SCAD) gene, promoting its transcription to enhance lipid oxidation. Moreover, FAM3D-FPR1 axis also activates calmodulin-Akt pathway to suppress gluconeogenesis in hepatocytes. In conclusion, hepatocyte-secreted FAM3D activated the FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation in hepatocytes. Under obesity conditions, increased hepatic FAM3D expression is a compensatory mechanism against dysregulated glucose and lipid metabolism.
Subject(s)
Hyperglycemia , Non-alcoholic Fatty Liver Disease , Animals , Humans , Mice , Butyryl-CoA Dehydrogenase/metabolism , Diet, High-Fat , Hepatocytes/metabolism , Heterogeneous-Nuclear Ribonucleoprotein U/metabolism , Hyperglycemia/metabolism , Lipid Metabolism , Lipids , Liver/metabolism , Mice, Inbred C57BL , Mice, Obese , Non-alcoholic Fatty Liver Disease/metabolism , Receptors, Formyl Peptide/metabolism , Receptors, Glucocorticoid/metabolismABSTRACT
AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 structural models of the 17 canonical members of the human PARP protein family and supplemented this analysis with new experiments and an overview of recent published data. PARP proteins are typically involved in the modification of proteins and nucleic acids through mono or poly(ADP-ribosyl)ation, but this function can be modulated by the presence of various auxiliary protein domains. Our analysis provides a comprehensive view of the structured domains and long intrinsically disordered regions within human PARPs, offering a revised basis for understanding the function of these proteins. Among other functional insights, the study provides a model of PARP1 domain dynamics in the DNA-free and DNA-bound states and enhances the connection between ADP-ribosylation and RNA biology and between ADP-ribosylation and ubiquitin-like modifications by predicting putative RNA-binding domains and E2-related RWD domains in certain PARPs. In line with the bioinformatic analysis, we demonstrate for the first time PARP14's RNA-binding capability and RNA ADP-ribosylation activity in vitro. While our insights align with existing experimental data and are probably accurate, they need further validation through experiments.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases , Humans , Poly(ADP-ribose) Polymerases/metabolism , Protein Domains , ADP-Ribosylation , RNA/metabolismABSTRACT
Previous studies only assessed the association between depressive symptoms and risk of preterm birth (PTB) at a time-point during pregnancy, resulting in inconsistent or contradictory results. Therefore, we aimed to explore the associations between the trajectories of depressive symptoms during pregnancy and risk of PTB. In total, 7732 pregnant women were included in 24 hospitals from 15 provinces of China. The Edinburgh Postpartum Depression Scale (EPDS) was used to evaluate depressive symptoms in the first, second, and third trimesters. Associations between depressive symptoms and risk of PTB were performed by group-based trajectory modeling (GBTM), propensity score-based inverse probability of treatment weighting (IPTW), and logistic regression. GBTM identified five trajectories: compared with persistently low-stable trajectory of depressive symptoms, women with moderate-stable (OR = 1.23, 95% CI: 1.02-1.76), high-falling (OR = 1.35, 95% CI: 1.11-2.21), moderate-rising (OR = 1.38, 95% CI: 1.06-2.04), and high-stable trajectory of depressive symptoms (OR = 1.40, 95% CI: 1.16-3.28) had an increased risk of PTB. In addition, the associations between trajectories of depressive symptoms and risk of PTB were most significant in multiparous women with a history of PTB. There was no difference in the risk of early-moderate PTB among different trajectories of depressive symptoms and only the risk of late PTB was different among different trajectories. In conclusion, the depressive symptoms of pregnant women were not constant during pregnancy, and different trajectories of depressive symptoms were associated with different risks of PTB.
Subject(s)
Pregnancy Complications , Premature Birth , Female , Pregnancy , Infant, Newborn , Humans , Depression/complications , Depression/epidemiology , Depression/diagnosis , Premature Birth/epidemiology , Prospective Studies , Risk Factors , Pregnancy Complications/epidemiology , Pregnancy Complications/diagnosis , ParityABSTRACT
TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn't prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.
Subject(s)
Lysine , Ubiquitin-Protein Ligases , Animals , Lysine/metabolism , Ubiquitination , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Protein Processing, Post-Translational , Proteolysis , Mammals/metabolismABSTRACT
The spatiotemporal visualization of intracellular microRNA (miRNA) plays a critical role in the diagnosis and treatment of malignant disease. Although DNAzyme-based biosensing has been regarded as the most promising candidate, inefficient analytical resolution is frequently encountered. Here, we propose a bioorthogonal approach toward high-fidelity imaging of intracellular miRNA by designing a multifunctional nanoprobe that integrates MnO2 nanosheet-mediated intracellular delivery and activation by a fat mass and obesity-associated protein (FTO)-switched positive feedback. MnO2 nanosheets facilitate nanoprobe delivery and intracellular DNAzyme cofactors are released upon glutathione-triggered reduction. Meanwhile, an m6A-caged DNAzyme probe could be bioorthogonally activated by intracellular FTO to eliminate potential off-target activation. Therefore, the activated DNAzyme probe and substrate probe could recognize miRNA to perform cascade signal amplification in the initiation of the release of Mn2+ from MnO2 nanosheets. This strategy realized high-fidelity imaging of intracellular aberrant miRNA within tumor cells with a satisfactory detection limit of 9.7 pM, paving the way to facilitate clinical tumor diagnosis and prognosis monitoring.
Subject(s)
DNA, Catalytic , MicroRNAs , Neoplasms , Humans , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Diagnostic Imaging , DNA, Catalytic/genetics , Manganese Compounds , MicroRNAs/genetics , Neoplasms/pathology , Oxides , Intracellular Space/geneticsABSTRACT
AIMS: We explored the complex relationships between pre-pregnancy body mass index (pBMI) and maternal or infant complications and the mediating role of gestational diabetes mellitus (GDM) in these relationships. METHODS: Pregnant women from 24 hospitals in 15 different provinces of China were enrolled in 2017 and followed through 2018. Propensity score-based inverse probability of treatment weighting, logistic regression, restricted cubic spline models, and causal mediation analysis were utilized. In addition, the E-value method was used to evaluate unmeasured confounding factors. RESULTS: A total of 6174 pregnant women were finally included. Compared to women with a normal pBMI, obese women had a higher risk for gestational hypertension (odds ratio [OR] = 5.38, 95% confidence interval [CI]: 3.48-8.34), macrosomia (OR = 2.65, 95% CI: 1.83-3.84), and large for gestational age (OR = 2.05, 95% CI: 1.45-2.88); 4.73% (95% CI: 0.57%-8.88%), 4.61% (95% CI: 0.51%-9.74%), and 5.02% (95% CI: 0.13%-10.18%) of the associations, respectively, were mediated by GDM. Underweight women had a high risk for low birth weight (OR = 1.42, 95% CI: 1.15-2.08) and small for gestational age (OR = 1.62, 95% CI: 1.23-2.11). Dose-response analyses indicated that 21.0 kg/m2 may be the appropriate tipping point pBMI for risk for maternal or infant complications in Chinese women. CONCLUSION: A high or low pBMI is associated with the risk for maternal or infant complications and partly mediated by GDM. A lower pBMI cutoff of 21 kg/m2 may be appropriate for risk for maternal or infant complications in pregnant Chinese women.
Subject(s)
Diabetes, Gestational , Female , Pregnancy , Infant , Humans , Diabetes, Gestational/epidemiology , Diabetes, Gestational/therapy , Longitudinal Studies , Body Mass Index , Cohort Studies , China/epidemiologyABSTRACT
BACKGROUND: Current guidelines recommend hepatocellular carcinoma (HCC) screening in high-risk populations. However, the ideal HCC screening interval and screening modality have not been determined. This study aimed to compare the screening efficacy among different modalities with various intervals. METHODS: PubMed and other nine databases were searched through June 30, 2021. Binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs). Survival rates were also pooled using RR with 95% CIs because most eligible studies only provided the number of survival patients instead of hazard ratio. RESULTS: In all, 13 studies were included. Two random controlled trials (RCTs) and six cohort studies compared screening intervals for ultrasonography (US) screening and found no significant differences between shorter (3- or 4-month) and longer (6- or 12-month) screening intervals in terms of early HCC proportion, HCC significant mortality, 1-year survival rate; screening at 6-month interval significantly increased the proportion of early HCC (RRâ=â1.17, 95% confidence interval [CI]: 1.08-1.26) and prolonged the 5-year survival rate (RRâ=â1.39, 95% CI: 1.07-1.82) relative to the 12-month interval results. Three other RCTs and two cohort studies compared different screening modalities in cirrhosis or chronic hepatitis B, which indicated no statistical differences in the proportion of early HCC (RRâ=â0.89, 95% CI: 0.40-1.96) and HCC mortality (RRâ=â0.69, 95% CI: 0.23-2.09) between the biannual US and annual computed tomography (CT screening). Biannual US screening showed a lower proportion of early HCC than biannual magnetic resonance imaging (MRI) (RRâ=â0.60, 95% CI: 0.37-0.97) and biannual US combined with annual CT (RRâ=â1.31, 95% CI: 1.13-1.51) screening. The proportion of early HCC in the contrast-enhanced US group was slightly higher than that in the B-mode US (RRâ=â1.08, 95% CI: 1.00-1.23) group. CONCLUSIONS: The evidence suggests that 6 months may be the best HCC screening interval for US screening. The effectiveness of CT and MRI is better than US during same screening intervals. However, MRI and CT are more expensive than US, and CT also can increase the risk of radiation exposure. The selection of CT or MRI instead of US should be carefully considered. REGISTRATION: No. CRD42020148258 at PROSPERO website ( https://www.crd.york.ac.uk/PROSPERO/ ).