Synthesis of a COF-on-MOF hybrid nanomaterial for enhanced colorimetric biosensing.

The construction of hybrid materials is significant for the exploration of functionalities in colorimetric biosensing due to its structural designability and synergy effects. In this work, a COF-on-MOF hybrid nanomaterial has been newly synthesized for colorimetric biosensing. Experimental results reveal that on-surface synthesis of COF on MOF brings nanoscale proximity between COF and MOF, which exhibits more than two folds of peroxidase-like activity as compared to single Fe-MOF. Therefore, by using the MCA@Fe-MOF nanomaterial with the assist of a specific acetyl-peptide, MCA@Fe-MOF can serve as an efficient signal reporter for colorimetric assay of histone deacetylase (HDAC), and the limit of detection (LOD) can be as low as 0.261 nM. Looking forward, the demand for diverse and promising COF-on-MOF nanomaterials with varied functionalities is anticipated, propelling further exploration of their role in colorimetric biosensing.

Endothelial lincRNA-p21 alleviates cerebral ischemia/reperfusion injury by maintaining blood-brain barrier integrity.

Blood-brain barrier (BBB) disruption is increasingly recognized as an early contributor to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury, and is also a key event in triggering secondary damage to the central nervous system. Recently, long non-coding RNA (lncRNA) have been found to be associated with ischemic stroke. However, the roles of lncRNA in BBB homeostasis remain largely unknown. Here, we report that long intergenic non-coding RNA-p21 (lincRNA-p21) was the most significantly down-regulated lncRNA in human brain microvascular endothelial cells (HBMECs) after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment among candidate lncRNA, which were both sensitive to hypoxia and involved in atherosclerosis. Exogenous brain-endothelium-specific overexpression of lincRNA-p21 could alleviate BBB disruption, diminish infarction volume and attenuate motor function deficits in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Further results showed that lincRNA-p21 was critical to maintain BBB integrity by inhibiting the degradation of junction proteins under MCAO/R and OGD/R conditions. Specifically, lincRNA-p21 could inhibit autophagy-dependent degradation of occludin by activating PI3K/AKT/mTOR signaling pathway. Besides, lincRNA-p21 could inhibit VE-cadherin degradation by binding with miR-101-3p. Together, we identify that lincRNA-p21 is critical for BBB integrity maintenance, and endothelial lincRNA-p21 overexpression could alleviate cerebral I/R injury in mice, pointing to a potential strategy to treat cerebral I/R injury.

Carbonate Ester-Based Electrolyte Enabling Rechargeable Zn Battery to Achieve High Voltage and High Zn Utilization.

Owing to the high H2O activity, the aqueous electrolyte in the Zn battery exhibits a narrow electrochemical window and inevitable hydrogen evolution reaction, limiting the anode utilization ratio and performance at high voltage. Carbonate ester, the well-developed electrolyte solvent in Li-ion batteries, exhibits aprotic properties and high anodic stability. However, its use in Zn metal batteries is limited due to the low solubility of Zn salts in carbonate esters. Herein, we propose a carbonate ester-based electrolyte (EC:DMC:EMC = 1:1:1 wt %), which contains a new Zn salt (Zn(BHFip)2) characterized by low cost, easy synthesis, and excellent aprotic solvent solubility. The BHFip- anion assists in forming Zn2+ conductive SEI on the anode and decomposes at high voltage to generate a protective CEI layer on the cathode. The Zn//Zn symmetric cell using such electrolyte achieves a remarkable Zn utilization ratio of 91% for 125 h, which has rarely been reported before. Furthermore, the Zn//LiMn2O4 full cell with an average operation voltage of 1.7 V demonstrates reliable cycling for 135 cycles with an N/P ratio of 1:1. In addition, the Zn//LiNi0.5Mn1.5O4 full cell exhibits a high discharge median voltage exceeding 2.2 V for 280 cycles, with the high voltage plateau (above 2 V) constituting 82% of the total capacity.

In Situ Self-Assembled Phytopolyphenol-Coordinated Intelligent Nanotherapeutics for Multipronged Management of Ferroptosis-Driven Alzheimer's Disease.

Ferroptosis is a vital driver of pathophysiological consequences of Alzheimer's disease (AD). High-efficiency pharmacological inhibition of ferroptosis requires comprehensive coordination of diverse abnormal intracellular events, which is an urgent problem and great challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified quercetin-derived smart nanomedicine (TQCN) is developed for multipronged anti-ferroptosis therapy in AD. Taking advantage of the favorable brain-targeting and mitochondria-locating properties, TQCN can efficiently chelate iron through phytopolyphenol-mediated spontaneous coordination and self-assemble into metal-phenolic nanocomplexes in situ, exerting escalating exogenous offensive effects to attenuate iron overload and its induced free radical burst. Meanwhile, the Nrf2 signaling-mediated endogenous defensive system is reconstituted to restore iron metabolism homeostasis represented by iron export and storage and enhance cytoprotective antioxidant cascades represented by lipid peroxidation detoxification. Benefiting from the multifaceted regulation of pathogenic processes triggering ferroptosis, TQCN treatment can ameliorate various neurodegenerative manifestations associated with brain iron deposition and rescue severe cognitive decline in AD mice. This work displays great promise of in situ self-assembled phytopolyphenol-coordinated intelligent nanotherapeutics as advanced candidates against ferroptosis-driven AD progression.

Gut microbiota and cognitive performance: A bidirectional two-sample Mendelian randomization.

PURPOSE: Previous studies have suggested a potential association between gut microbiota and neurological and psychiatric disorders. However, the causal relationship between gut microbiota and cognitive performance remains uncertain. METHODS: A two-sample Mendelian randomization (MR) study used SNPs linked to gut microbiota (n = 18,340) and cognitive performance (n = 257,841) from recent GWAS data. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were employed. Heterogeneity was assessed via Cochran's Q test for IVW. Results were shown with funnel plots. Outliers were detected through leave-one-out method. MR-PRESSO and MR-Egger intercept tests were conducted to address horizontal pleiotropy influence. LIMITATIONS: Limited to European populations, generic level, and potential confounding factors. RESULTS: IVW analysis revealed detrimental effects on cognitive perfmance associated with the presence of genus Blautia (P = 0.013, 0.966[0.940-0.993]), Catenibacterium (P = 0.035, 0.977[0.956-0.998]), Oxalobacter (P = 0.043, 0.979[0.960-0.999]). Roseburia (P < 0.001, 0.935[0.906-0.965]), in particular, remained strongly negatively associated with cognitive performance after Bonferroni correction. Conversely, families including Bacteroidaceae (P = 0.043, 1.040[1.001-1.081]), Rikenellaceae (P = 0.047, 1.026[1.000-1.053]), along with genera including Paraprevotella (P = 0.044, 1.020[1.001-1.039]), Ruminococcus torques group (P = 0.016, 1.062[1.011-1.115]), Bacteroides (P = 0.043, 1.040[1.001-1.081]), Dialister (P = 0.027, 1.039[1.004-1.074]), Paraprevotella (P = 0.044, 1.020[1.001-1.039]) and Ruminococcaceae UCG003 (P = 0.007, 1.040[1.011-1.070]) had a protective effect on cognitive performance. CONCLUSIONS: Our results suggest that interventions targeting specific gut microbiota may offer a promising avenue for improving cognitive function in diseased populations. The practical application of these findings has the potential to enhance cognitive performance, thereby improving overall quality of life.

A Meta-Analysis of the Prevalence of Children Goiter in High Water Iodine Areas of China.

Although there are now a large number of studies confirming that high iodine levels can cause goiter, there is controversy and a lack of quantitative data. A systematic search of PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and China Biomedical Database for literature on high iodine and goiter in children was performed with a time limit from January 2013 to October 2023. After screening the literature based on the inclusion criteria, extracting the literature data, and evaluating the risk of bias of the included studies, a single-arm meta-analysis was performed using R 4.0.4 software. Twenty-three studies with a total of 50,980 subjects were included. Meta-analysis showed that the prevalence of goiter among children in water-borne iodine-excess areas was 6.0% [95% CI (4.3%, 7.6%)], and subgroup analyses showed that the prevalence of goiter in children with water iodine 100.1-150 µg/L, 150.1-300 µg/L, and > 300 µg/L was 7.5% [95% CI (0.0%, 15.8%)], 5.5% [95% CI (3.1%, 8.0%)], and 10.2% [95% CI (6.7%, 13.6%)], respectively, and the difference was statistically significant (P < 0.01); The prevalence of goiter among children in the northern China (5.8% [95% CI (4.1%, 7.5%)]) was higher than that in the southern China (3.5% [95% CI (1.0%, 6.0%)]) (P < 0.01); the prevalence of goiter in children with urinary iodine levels 100-199 µg/L, 200-299 µg/L, and ≥ 300 µg/L was 2.4% [95% CI (1.9%, 2.9%)], 3.3% [95% CI (1.9%, 4.8%)], and 7.3% [95% CI (4.4%, 9.9%)], respectively, the difference was statistically significant (P < 0.01); the prevalence of goiter in children aged 8, 9, 10, 11, and 12 years old was 5.1% [95% CI (3.9%, 6.4%)], 8.0% [95% CI (4.0%, 11.9%)], 6.2% [95% CI (3.9%, 8.5%)], 5.5% [95% CI (0.0%, 13.2%)], and 5.4% [95% CI (0.0%, 15.1%)], and when age ≥ 9 years, the relationship between goiter prevalence and age showed a trend toward decreasing with age, but the relationship between different age was no statistical difference in the prevalence of goiter between ages. urinary iodine. The prevalence of goiter in children was higher in areas with high water iodine; the prevalence of goiter in children in the north was significantly higher than that in the south; the prevalence of goiter in children tends to increase with increased urinary iodine levels.

Activating Organic Electrode via Trace Dissolved Organic Molecules.

Organic electrode materials have gained attention for their tunable structures and sustainability, but their low electronic conductivity requires the use of large amounts of carbon additives (30 wt %) and low mass loadings (<2 mg cm-2) in electrodes. Here, we synthesize dibenzo[b,i]phenazine-5,7,12,14-tetrone (DPT) as a cathode active material for an aqueous Zn battery and find that Zn2+ storage dominates the cathode reaction. This battery demonstrates high capacity (367 mAh g-1), high-rate performance, and superlong life (12000 cycles). Remarkably, despite DPT's insulative nature, even with a high mass loading (10 mg cm-2) and only 10 wt % carbon additives, the DPT-based cathode exhibits promising performance due to trace dissolved discharge product (DPTx-). During discharge, the DPT is reduced to trace amounts of dissolved DPTx- at the cathode surface, which in turn reduces the remaining solid DPT as a redox mediator. Furthermore, dissolution-redeposition results in the reduction of DPT size and the formation of pores, further activating the electrode.

Proximity Amplification-Enabled Electrochemical Analysis of Tumor-Associated Glycoprotein Biomarkers.

Glycoproteins produced and secreted from specific cells and tissues are associated with several diseases and emerge as typical biomarkers to provide useful information in cancer diagnosis considering their abnormal expression levels. In this work, we design a universal method to achieve the accurate and sensitive analysis of tumor-associated glycoprotein biomarkers based on both carbohydrate recognition and protein recognition at the same protein surface. The byproduct of dual recognition-induced proximity amplification, pyrophosphate, triggers the disassembly of methylene blue-encapsulated metal-organic frameworks, MB@ZIF-90. As a result, methylene blue molecules are released to arouse amplified electrochemical responses for glycoprotein analysis. Experimental results demonstrate the high-accuracy analysis of carcinoembryonic antigen, a typical glycoprotein biomarker in cancer diagnosis, in a linear range of 0.001-100 ng mL-1 with a low limit of detection of 0.419 pg mL-1. The method also displays satisfactory specificity and recoveries in complex serum samples and proves good versatility by adopting two other tumor-associated glycoprotein biomarkers, α-fetoprotein and mucin-1, as the targets. Therefore, this work provides a valuable tool for the analysis of glycoprotein biomarkers, which may be of great potential in early warning of malignant tumors in clinical applications.

Mechanisms of DHEA-induced AMH increase in the ovarian tissues of PCOS rat.

The present study aimed to build a DHEA-induced polycystic ovary syndrome (PCOS) rat model to evaluate the potential mechanism of DHEA-induced AMH rise in these rat ovarian tissues. A total of 36 female 3-week-old rats were allocated into two groups at random. The control group received merely the same amount of sesame oil for 20 days while the experimental group received 0.2 mL of sesame oil Plus DHEA 6 mg/100 g daily. Both groups' vaginal opening times were noted, and vaginal smears were taken. By using RT-qPCR and Western blot, the mRNA and protein expression of AMH, GATA4, SF1, and SOX9 in the ovarian tissues of the two groups was investigated.The rats in the experimental group appeared to have obvious disorders of the estrus cycle, as evidenced by the ratio of estrus being significantly higher than that in the control group (P < 0.05); HE staining revealed that the ovarian volume, follicular vacuoles, and follicular lumen of the rats in the experimental group increased significantly.The ELISA results revealed that T and AMH in the experimental group were higher than those in the control group at day 15 and 20. AMH、GATA4 and SF1 mRNA and protein expression were higher in the experimental group than in the control group on day 15 and 20 (P < 0.05). On day 20, the experimental group outperformed the control group (P < 0.05). In the DHEA-induced PCOS rat model, androgen may have enhanced AMH expression via increasing the expression of genes associated to the AMH promoter binding site (GATA4, SF1, SOX9).

Activating Transcription Factor 4-mediated Mitochondrial Unfolded Protein Response Alleviates Hippocampal Neuronal Damage in an In Vitro Model of Epileptiform Discharges.

The mitochondrial unfolded protein response (mtUPR) has been shown to restore protein homeostasis and cell function under stress, and recent studies have confirmed that the activating transcription factor 4 (ATF4) regulates mtUPR. However, the role of ATF4-mediated mtUPR in a hippocampal neuronal culture model of seizures remains unclear. Our results showed that the expression of mtUPR-related proteins (HSP60 and CLpP) increased in primary hippocampal neurons with seizures induced by a magnesium-free solution, suggesting mtUPR activation. Furthermore, ATF4 overexpression by lentiviral vector transfection enhanced the expression of HSP60 and CLpP, whereas ATF4 low expression by lentiviral vector transfection weakened the expression of HSP60 and CLpP. In addition, ATF4 overexpression increased neuronal viability and reduced seizure-induced apoptosis. ATF4 overexpression reduced reactive oxygen species (ROS) production and improved mitochondrial membrane potential damage during seizures. Moreover, ATF4 overexpression reduced the BCL2-associated X protein (Bax) expression and increased the expression of B-cell lymphoma 2 (BCL2). In contrast, ATF4 expression showed the opposite trend. In conclusion, our results showed that ATF4-mediated mtUPR may delay the cascade activation of apoptotic pathways by reducing ROS-mediated oxidative stress, thereby attenuating seizure-induced stress injury.

Abbreviated Versus Full-Protocol MRI for Breast Cancer Neoadjuvant Chemotherapy Response Assessment: Diagnostic Performance by General and Breast Radiologists.

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

Identification of single nucleotide polymorphisms by a peptide nucleic acid-based sandwich hybridization assay coupled with toehold-mediated strand displacement reactions.

In this work, we developed a simple and accurate peptide nucleic acid (PNA)-based sandwich hybridization assay for single nucleotide polymorphisms (SNPs) in the p53 gene. Our approach combines the enzyme-free toehold-mediated strand displacement reaction (SDR) with real-time enzyme-linked immunosorbent assay (ELISA) to detect SNPs with high sensitivity and specificity. A PNA-DNA heteroduplex with an external toehold is designed and fixed on well surface of a 96-well plate. The strand displacement from PNA-DNA heteroduplexes is initiated by the hybridization of target sequence with the toehold domain and ends with the fully displacing of the incumbent DNA. Finally, the as formed PNA-target DNA duplex with overhang at its 5'-end hybridizes with a biotin-labeled reporter PNA to form a sandwich structure on surface for signal amplification. The proposed PNA-based sandwich biosensor displays high sensitivity and greatly enhanced discriminability to target p53 gene segments against single-base mutant sequences compared to its all-DNA counterpart. Furthermore, the probe design is elegantly simple and the sensing procedure is easy to operate. We believe that this strategy may provide a simple and universal strategy for SNPs detection through easily altering the sequences of probes according to the sequences around target SNPs.

ATF5 Attenuates Apoptosis in Hippocampal Neurons with Seizures Evoked by Mg2+-Free Medium via Regulating Mitochondrial Unfolded Protein Response.

The mitochondrial unfolded protein response (mtUPR)-a stress response pathway for maintaining protein homeostasis-is critical in seizures-induced neuronal injury. The activating transcription factor 5 (ATF5) regulates mtUPR; however, whether ATF5-regulated mtUPR has a role in neuronal injury in epilepsy remains uncertain. Here, we investigated the effects of ATF5-regulated mtUPR on neuronal injury in hippocampal neurons with seizures evoked by Mg2+-free medium. HSP60 and ClpP, key proteins of mtUPR, were upregulated, indicating mtUPR activation. ATF5 overexpression by lentiviral vector infection potentiated mtUPR, whereas ATF5 downregulation by lentiviral vector infection attenuated this response. Moreover, ATF5 overexpression elevated mitochondrial membrane potential and reduced reactive oxygen species (ROS) generation, suggesting that ATF5 overexpression protected mitochondrial homeostasis, while ATF5 downregulation had the opposite effect. ATF5 overexpression also reversed Bcl2 downregulation and Bax upregulation and attenuated seizures-induced neuronal apoptosis, while ATF5 downregulation aggravated the injury. Our study demonstrates that ATF5 attenuates seizures-induced neuronal injury, possibly by regulating mtUPR pathways, to prevent mitochondrial dysfunction.

Synthesis of Zn2+-Pre-Intercalated V2O5·nH2O/rGO Composite with Boosted Electrochemical Properties for Aqueous Zn-Ion Batteries.

Layered vanadium-based materials are considered to be great potential electrode materials for aqueous Zn-ion batteries (AZIBs). The improvement of the electrochemical properties of vanadium-based materials is a hot research topic but still a challenge. Herein, a composite of Zn-ion pre-intercalated V2O5·nH2O combined with reduced graphene oxide (ZnVOH/rGO) is synthesized by a facile hydrothermal method and it shows improved Zn-ion storage. ZnVOH/rGO delivers a capacity of 325 mAh·g-1 at 0.1 A·g-1, and this value can still reach 210 mAh·g-1 after 100 cycles. Additionally, it exhibits 196 mAh·g-1 and keeps 161 mAh·g-1 after 1200 cycles at 4 A·g-1. The achieved performances are much higher than that of ZnVOH and VOH. All results reveal that Zn2+ as "pillars" expands the interlayer distance of VOH and facilitates the fast kinetics, and rGO improves the electron flow. They both stabilize the structure and enhance efficient Zn2+ migration. All findings demonstrate ZnVOH/rGO's potential as a perspective cathode material for AZIBs.

Covalent organic frameworks (COFs)-based biosensors for the assay of disease biomarkers with clinical applications.

Covalent organic frameworks (COFs) are an emerging type of porous crystalline polymers that are built by light elements (typically H, B, C, N, O and Si) via organic covalent bonds. Currently, COFs have been exploited for biomedical application due to their unique properties, such as structural diversity, intrinsic stability, ordered porosity, tailor-made functions, and excellent adsorption features. In particular, COFs are increasingly popular in the construction of biosensors for the detection of various disease biomarkers, and have been extended to the clinical applicability for early diagnostics, medication instruction and prognostic monitoring of diseases. In this review, we mainly summarize the recent advances on COFs-based biosensors for the assay of disease biomarkers with clinical applications. According to the features of molecular structure, disease biomarkers are classified into four categories, including small biological ions/molecules, proteins, nucleic acids, and cancer cells/exosomes. Impressively, COFs-based biosensors present a bright prospect in clinical diagnosis of diseases in both hospital-end and household-end utilization.

Molecular Characterization of Exosomes for Subtype-Based Diagnosis of Breast Cancer.

Breast cancer is very heterogeneous and the most frequently diagnosed cancer worldwide, and precise therapy targeting specific subtypes may improve the survival rates of breast cancer patients. In this study, we designed a biomimetic vesicle by camouflaging catalytic DNA machinery with a breast cancer cell membrane, which enabled the molecular classification of circulating exosomes for subtype-based diagnosis through homotypic recognition. In addition, the vesicles specifically targeted and fused with breast cancer exosomes with phenotypic homology and manipulated the DNA machinery to amplify electrochemical signaling using exosomal RNA as an endogenous trigger. The biomimetic vesicles prepared with MCF-7 cancer cell-derived membranes were shown to recognize estrogen receptor-positive breast cancer exosomes and exhibited a low detection limit of 557 particles mL-1 with microRNA-375 used as the endogenous biomarker. Furthermore, the biomimetic vesicles prepared with MDA-MB-231 cancer cell-derived membranes displayed satisfactory performance in a homotypic analysis of triple-negative breast cancer exosomes with a potential therapeutic target, PD-L1 mRNA, used as the endogenous biomarker. Most importantly, cross-validation experiments confirmed the high accuracy and selectivity of this homotypic recognition-driven analysis for molecular subtyping of breast cancer. When applied to clinical samples of breast cancer patients, the vesicles demonstrated feasibility and reliability for evaluating the molecular features of cancer cell-derived exosomes and enabled stage-specific monitoring of breast cancer patients because the electrochemical signals showed a positive correlation with disease progression. Therefore, this work may provide new ideas for the precise diagnosis and personalized treatment of breast cancer patients throughout the whole disease process.

Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in Caenorhabditis elegans.

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant defects in the degradation of apoptotic cells, demonstrating the importance of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, the adaptor protein CED-6, and the large GTPase dynamin (DYN-1) promotes the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex components. Further observations suggest that autophagosomes provide apoptotic cell-degradation activities in addition to and in parallel of lysosomes. Our findings reveal that, unlike the single-membrane, LC3-associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, the canonical double-membrane autophagosomes facilitate the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream signaling molecules that initiate this crosstalk.

An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor.

Mutations in HNF1A are associated with Maturity Onset Diabetes of the Young type 3 (MODY3) and most of them are in the coding region. Herein, we identified an intron mutation at the 6th nucleotide upstream of the end of intron 7 of HNF1A, named IVS7-6G > A, in a patient with early-onset diabetes. The "minigene" assay showed that IVS7-6G > A produced two aberrant mRNA variants translating into two truncated proteins: L502S fs* and G437A fs*, both affecting HNF1A transactivation domain (TAD). To determine functional consequences of IVS7-6G > A mutation, we made plasmids encoding truncated HNF1A containing different portions of HNF1A TAD and found that the TAD of HNF1A is important not only for its regulatory activities, but also for its nuclearization, and the residues 282-501 was more essential than 502-631. Our data suggested IVS7-6G > A impaired HNF1A splicing and may contribute to the pathogenesis of MODY3.

Recent Advances in Bio-Sensing Methods for the Detection of Tumor Exosomes.

Exosomes, small vesicles with the diameters of 40-160 nm, play an important role in intercellular transport and communication. Exosomes are rich in many kinds of biomolecules, and differential expression of exosomal contents directly reflects the state of the original cells. Therefore, the tumor exosomes are appearing as promising biomarkers in liquid biopsy, and highly sensitive and specific detection of tumor exosomes may provide the information for the early diagnosis, real-time monitoring and treatment of the tumors. In this review, we summarized the recent advances in the detection of tumor exosomes, mainly focusing on the use of different analytical techniques, such as optical and electrochemical methods as well as that combination with newly-emerging microfluidic techniques, thereby providing valuable information for the application in the clinical diagnosis and management of the tumors.

Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model.

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1[Formula: see text] and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1[Formula: see text] and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.