The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.

Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.

Lycium barbarum polysaccharide mitigated methamphetamine addiction and altered methamphetamine-induced gut microbiota dysbiosis.

Methamphetamine (MA) is a highly addictive mental stimulant, and MA abuse remains a significant public health problem worldwide, while effective treatment options are limited. Lycium barbarum polysaccharide (LBP), a major effective component extracted from Lycium barbarum, has potential health-promoting effects on the nervous system; however, its role in MA dependence remains unclear. In this study, the conditioned place preference (CPP) of MA addiction in adult male mice was established to detect changes in gut microbiota profiles after LBP treatment through 16S rRNA gene sequencing. Our results found that LBP administration could alleviate MA-induced CPP and hyperactivity. Interestingly, LBP improved MA-induced gut microbiota dysbiosis by increasing some beneficial autochthonous genus abundances, such as Allobaculum, Gordonibacter, and Ileibacterium. MA exposure induced the co-occurrence network of intestinal microbiota to become weaker and more unstable when compared with the control group, while LBP changed the above effects when compared with the MA group. Bacterial gene function prediction showed that amphetamine addiction, cocaine addiction, and short-chain fatty acid metabolism were enriched. These findings reveal that LBP might regulate MA-induced gut microbiota and behavior changes, which showed potential therapeutic applicability in treating MA addiction by regulating the gut microbiota.

Proteomic analysis discovers potential biomarkers of early traumatic axonal injury in the brainstem.

OBJECTIVE: Application of Tandem Mass Tags (TMT)-based LC-MS/MS analysis to screen for differentially expressed proteins (DEPs) in traumatic axonal injury (TAI) of the brainstem and to predict potential biomarkers and key molecular mechanisms of brainstem TAI. METHODS: A modified impact acceleration injury model was used to establish a brainstem TAI model in Sprague-Dawley rats, and the model was evaluated in terms of both functional changes (vital sign measurements) andstructural changes (HE staining, silver-plating staining and ß-APP immunohistochemical staining). TMT combined with LC-MS/MS was used to analyse the DEPs in brainstem tissues from TAI and Sham groups. The biological functions of DEPs and potential molecular mechanisms in the hyperacute phase of TAI were analysed by bioinformatics techniques, and candidate biomarkers were validated using western blotting and immunohistochemistry on brainstem tissues from animal models and humans. RESULTS: Based on the successful establishment of the brainstem TAI model in rats, TMT-based proteomics identified 65 DEPs, and bioinformatics analysis indicated that the hyperacute phase of TAI involves multiple stages of biological processes including inflammation, oxidative stress, energy metabolism, neuronal excitotoxicity and apoptosis. Three DEPs, CBR1, EPHX2 and CYP2U1, were selected as candidate biomarkers and all three proteins were found to be significantly expressed in brainstem tissue 30 min-7 days after TAI in both animal models and humans. CONCLUSION: Using TMT combined with LC-MS/MS analysis for proteomic study of early TAI in rat brainstem, we report for the first time that CBR1, EPHX2 and CYP2U1 can be used as biomarkers of early TAI in brainstem by means of western blotting and immunohistochemical staining, compensating for the limitations of silver-plating staining and ß-APP immunohistochemical staining, especially in the case of very short survival time after TAI (shorter than 30 min). A number of other proteins that also have a potential marker role are also presented, providing new insights into the molecular mechanisms, therapeutic targets and forensic identification of early TAI in brainstem.

Effects of chronic triclosan exposure on nephrotoxicity and gut microbiota dysbiosis in adult mice.

Triclosan (TCS), a broad-spectrum, lipophilic, and antibacterial agent, has been commonly used in cosmetics, medical devices, and household products. The toxicity of TCS has recently become a research hotspot. Emerging evidence has shown that TCS can easily migrate to humans and animals and cause adverse effects on various target organs. However, the effects of TCS exposure on nephrotoxicity and underlying mechanisms remain unknown. The aim of the present study was to explore TCS-induced nephrotoxicity. Therefore, we establish a mouse model based on adult male mice to explore the effects of 10-week TCS exposure (50 mg/kg) on kidney. After mice were sacrificed, their blood, feces, and renal tissues were harvested for further analysis. We found that TCS treatment dramatically caused kidney structural damage, and increased blood urea nitrogen (BUN) and creatinine (Cr) expression levels, which indicated renal dysfunction. In addition, TCS exposure increased the malondialdehyde (MDA) and decreased superoxide dismutase (SOD) and total cholesterol (TCHO) expression levels, which indicated oxidative stress and lipid metabolism changes. The RNA sequencing (RNA-seq) of kidney tissue identified 221 differentially expressed genes (DEGs) enriched in 50 pathways, including drug metabolism-other enzymes, oxidative phosphorylation, glutathione metabolism, and inflammatory mediator regulation of TRP channels signaling pathways. The full-length 16S rRNA gene sequencing results showed that TCS exposure altered the community of gut microbiota, which was closely related to renal function damage. The above findings provide new insights into the mechanism of TCS-induced nephrotoxicity.

The Role of Non-coding RNAs in Methamphetamine-Induced Neurotoxicity.

Methamphetamine (METH) is an amphetamine-type stimulant that is highly toxic to the central nervous system (CNS). Repeated intake of METH can lead to addiction, which has become a globalized problem, resulting in multiple public health and safety problems. Recently, the non-coding RNA (ncRNA) has been certified to play an essential role in METH addiction through various mechanisms. Herein, we mainly focused on three kinds of ncRNAs including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which are involved in neurotoxicity effects such as cognitive impairment, behavioral abnormalities, and psychiatric disorders due to METH abuse. In addition, differential expression (DE) ncRNAs also suggest that specific responses and sensitivity to METH neurotoxicity exist in different brain regions and cells. We summarized the relationships between the ncRNAs and METH-induced neurotoxicity and psychiatric disturbances, respectively, hoping to provide new perspectives and strategies for the prevention and treatment of METH abuse. Schematic diagram of the non-coding RNAs (ncRNAs) was involved in methamphetamine (METH)-induced neurotoxicity. The ncRNAs were involved in METH-induced blood-brain barrier disruption, neuronal, astrocyte, and microglial damage, and synaptic neurotransmission impairment. The study of ncRNAs is a hot spot in the future to further understand the neurotoxicity of METH and provide more favorable scientific support for clinical diagnosis and innovation of related treatments.

A Versatile Assembly Approach toward Multifunctional Supramolecular Poly(Ionic Liquid) Nanoporous Membranes in Water.

Hydrogen (H)-bonding-integration of multiple ingredients into supramolecular polyelectrolyte nanoporous membranes in water, thereby achieving tailor-made porous architectures, properties, and functionalities, remains one of the foremost challenges in materials chemistry due to the significantly opposing action of water molecules against H-bonding. Herein, a strategy is described that allows direct fusing of the functional attributes of small additives into water-involved hydrogen bonding assembled supramolecular poly(ionic liquid) (PIL) nanoporous membranes (SPILMs) under ambient conditions. It discloses that the pore size distributions and mechanical properties of SPILMs are rationally controlled by tuning the H-bonding interactions between small additives and homo-PIL. It demonstrates that, benefiting from the synergy of multiple noncovalent interactions, small dye additives/homo-PIL solutions can be utilized as versatile inks for yielding colorful light emitting films with robust underwater adhesion strength, excellent stretchability, and flexibility on diverse substrates, including both hydrophilic and hydrophobic surfaces. This system provides a general platform for integrating the functional attributes of a diverse variety of additives into SPILMs to create multifunctional and programmable materials in water.

Combined exposure to polyvinyl chloride and polystyrene microplastics induces liver injury and perturbs gut microbial and serum metabolic homeostasis in mice.

A variety of microplastics (MPs) have become ubiquitous environmental pollutants, leading to inevitable human contact and health impacts. Most previous research has explored the toxic effects of a single type of MPs exposure. However, the effects of co-exposure to both common types of MPs, polyvinyl chloride (PVC) and polystyrene (PS) MPs on mammals have not been explored. Here, adult mice were exposed to PS-PVC (1.0 µm PS and 2.0 µm PVC both at the concentration of 0.5 mg/day) for 60 days. The results showed that PS-PVC co-exposure-induced hepatotoxicity was evidenced by liver histopathological changes, the release of inflammatory cytokines, and the activation of oxidative stress. Moreover, the intestinal mucosal barrier was damaged after PS-PVC treatment. The results of 16S rRNA gene sequencing reported there was a marked shift in the gut microbial structure accompanied by decreased relative abundances of probiotics, such as Clostridium, Lachnospiraceae_UCG-006, Desulfovibrio, Clostridiales_unclassified and Ruminococcaceae_unclassified and increased the conditional pathogen abundances, such as Erysipelatoclostridium. Furthermore, the triglyceride (TG) and total cholesterol (TCH) expression levels in the serum and liver were increased after PS-PVC co-exposure. Serum metabolomics analysis showed that there were 717 differential expression metabolites found in the positive- and negative-ion modes, including 476 up-regulated and 241 down-regulated, mainly enriched in butyrate metabolism, thiamine metabolism, and phenylacetate metabolism. In addition, remarked changes in the gut microbiota and serum metabolic profiles were closely related to hepatic and intestinal injuries after PS-PVC co-exposure. These results have provided new insights into the toxic effects of PS and PVC MPs co-exposure through the gut-liver axis and the health risks of PS and PVC MPs should be paid more attention to humans.

Polystyrene micro- and nanoparticles exposure induced anxiety-like behaviors, gut microbiota dysbiosis and metabolism disorder in adult mice.

Plastics have been proven to be a potential threat to the ecosystem, and their toxicity mechanism is still uncertain. In the ecological environment, plastics can be degraded into microplastics (MPs) and nanoplastics (NPs), which can be contaminated and ingested through the food chain. MPs and NPs are associated with severe intestinal injury, intestinal microbiota disorder, and neurotoxicity, but it is still unclear whether MPs- and NPs-induced intestinal microbiota dysbiosis will affect the brain through the gut-brain axis. In the current study, we determined the effects of exposure to polystyrene (PS)-MPs and PS-NPs on anxiety-like behaviors and explored the underlying mechanisms. This study explored the behavioral effects of 30-day and 60-day exposure to PS-NPs and PS-MPs using the open field test (OFT) and elevated plus maze (EPM) test. Behavioral tests showed PS-NPs and PS-MPs treatment remarkedly induced anxiety-like behaviors compared with the control group. Using 16 S rRNA gene sequencing and untargeted metabolomics analyses, we observed that PS-MPs and PS-NPs exposure reduced the beneficial gut microbiota expression level, such as Lachnoclostridium and Lactobacillus, and increased the conditionally pathogenic bacteria expressions level, such as Proteobacteria, Actinobacteria, and Desulfovibrio. In addition, PS-NPs and PS-MPs reduce intestinal mucus secretion and increase intestinal permeability. The results of serum metabonomics suggested that the metabolic pathways, such as ABC transporter pathways, aminoacyl-tRNA biosynthesis, biosynthesis of amino acids, and bile secretion were enriched after PS-NPs and PS-MPs treatment. Besides, neurotransmitter metabolites were also altered by PS-NPs and PS-MPs. It is noteworthy that the correlation analysis showed that the disorder of intestinal microbiota was related to anxiety-like behaviors and neurotransmitter metabolites disorder. The regulation of intestinal microbiota may be a promising treatment strategy for PS-MPs- and PS-NPs-induced anxiety disorder.

Pathological Changes and Cause of Death Associated with the Global Novel Coronavirus Disease (COVID-19).

The coronavirus disease 2019 (COVID-19) has been a global epidemic for more than three years, causing more than 6.9 million deaths. COVID-19 has the clinical characteristics of strong infectivity and long incubation period, and can cause multi-system damage, mainly lung damage, clinical symptoms of acute respiratory distress syndrome (ARDS) and systemic multiple organ damage. The SARS-CoV-2 virus is still constantly mutating. At present, there is no global consensus on the pathological changes of COVID-19 associated deaths and even no consensus on the criteria for determining the cause of death. The investigation of the basic pathological changes and progression of the disease is helpful to guide the clinical treatment and the development of therapeutic drugs. This paper reviews the autopsy reports and related literature published worldwide from February 2020 to June 2023, with a clear number of autopsy cases and corresponding pathological changes of vital organs as the inclusion criteria. A total of 1 111 autopsy cases from 65 papers in 18 countries are included. Pathological manifestations and causes of death are classified and statistically analyzed, common pathological changes of COVID-19 are summarized, and analytical conclusions are drawn, suggesting that COVID-19 infection can cause life-threatening pathological changes in vital organs. On the basis of different health levels of infected groups, the direct cause of death is mainly severe lung damage and secondary systemic multiple organ failure.

Large-Scale and Controllable Syntheses of Covalently-Crosslinked Poly(ionic liquid) Nanoporous Membranes.

Herein, we report an exciting synthetic procedure for the scalable and controllable fabrication of covalently crosslinked poly(ionic liquid) (PIL) nanoporous membranes (CPILMs) in water solution under ambient conditions. We found that the pore sizes, flexibility and compositions of freestanding CPILMs can be finely tailored by a rational structural choice of PIL, diketone and aldehyde. Studies on the CPILM formation mechanism revealed that hydrogen bonding-induced phase separation of amino-functionalized homo-PIL between its polar and apolar domains coupled with structural rearrangements due to the Debus Radsizewski reaction-triggered ambient covalent crosslinking process created a stable three-dimensionally interconnected pore system in water solution. Employing structurally stable CPILMs in ion sieving devices resulted in an excellent Li+ /Mg2+ separation efficiency due to the positively charged nature and "Donann" effects. This green, facile yet versatile approach to the production of CPILMs is a conceptually distinct and commercially interesting strategy for making useful nanoporous functional polyelectrolyte membranes.

Orbital apex syndrome secondary to apical periodontitis of a tooth: a case report.

BACKGROUND: Orbital apex syndrome (OAS) is a rare disease with a noticeable mortality rate. Although its etiology has been repeatedly assessed, few reports have concentrated on odontogenic infection. We presented a rare case of OAS secondary to apical periodontitis. CASE PRESENTATION: A 61-year-old male was admitted to our hospital for a 3-day history of left orbital and head pain, along with diplopia for 1-day. He also had toothache symptoms before his admission. Due to the atypical early symptoms of orbital apex and cranial nerve injury, no timely and effective diagnosis and treatment were initially provided. However, as the disease progressed and complications occurred, we timely adjusted the diagnosis and successfully controlled the infection. During the one-year follow-up, no recurrence of inflammation was observed; nevertheless, the ptosis and ophthalmoplegia persisted. CONCLUSIONS: OAS is a rare, while severe complication of odontogenic infection. This case had various symptoms and nerve injury in the orbital apical area. When disease is atypical in its early stages, treatment is easily overlooked. Early detection and suspicion of orbital apex-related complications should be heightened.

Safety and efficacy of low-dose rt-PA with tirofiban to treat acute non-cardiogenic stroke: a single-center randomized controlled study.

BACKGROUND AND PURPOSE: The recanalization rate after intravenous thrombolysis (IVT) is not enough and there is still the possibility of re-occlusion. We aim to investigate the effectiveness and safety of infusing tirofiban after IVT. METHODS: We performed a prospective controlled study of 60 patients with acute non-cardiogenic ischemic stroke who were hospitalized in Yantai Yuhuangding Hospital from January 2018 to December 2019. The patients were divided into 2 groups: those who received tirofiban for 24 h after IVT (rt-PA + T group) and those who did not receive postprocedural intravenous tirofiban (rt-PA group). The rt-PA + T group received low-dose rt-PA (0.6 mg/kg). The rt-PA group received standard dose rt-PA (0.9 mg/kg). The main outcome measure were safety, included the symptomatic intracranial hemorrhage (sICH), any ICH, severe systemic bleeding, and mortality. The secondary outcome measure is curative efficacy which were evaluated by the 7d-NIHSS score and functional outcomes at 90 days. During hospitalization, the deterioration of neurological function was recorded. RESULTS: All patients completed the follow-up with complete data, there were 30 patients in each of groups. The general characteristics between the two group patients had no statistically significant differences. Compared with the rt-PA + T group and the rt-PA group, in terms of safety, the rates of the sICH, severe systemic bleeding, and mortality in both groups were 0, and there was no statistically significant difference in the rates of any ICH between the two groups (10.0% vs. 3.3%, P = 0.306). In terms of efficacy, the rate of the early neurological deterioration events (END) was no statistical significance (0 vs. 6.6%, P = 0.246). There was no significant difference in the NIHSS score between the two groups before the IVT, and also at 24 h, however, the 7d-NIHSS score was lower in the rt-PA + T group compared with the rt-PA group (2.33 ± 1.85 vs. 4.80 ± 4.02, P = 0.004). At 90 days, 83.3% of patients in the rt-PA + T group had favorable functional outcomes compared with 60.0% of patients in the rt-PA group (P = 0.045). CONCLUSIONS: Low-dose rt-PA combined with tirofiban in acute non-cardiogenic ischemic stroke did not increase the risk of ICH, and mortality, and it was associated with neurological improvement. TRIAL REGISTRATION: The trial has been registered at the ChiCTR and identified as ChiCTR1800014666 (28/01/2018).

Polyvinyl chloride microplastics induced gut barrier dysfunction, microbiota dysbiosis and metabolism disorder in adult mice.

Microplastics (MPs) are a new kind of environmental pollutant that has attracted extensive attention in recent years. MPs can be ingested by multiple organisms and mainly accumulate in the intestine. However, there is still little known about the toxic effects of MPs on humans. Here, we chose the male adult mice as the research model, which were exposed to 2 µm polyvinyl chloride (PVC) MPs at a concentration of 100 mg/kg for consecutive 60 days, to study the toxicity of PVC-MPs. The changes in gut histology, enzymatic biomarkers, the intestinal microbiome, and metabolomic responses were monitored in mice. The results displayed that the PVC-MPs reduced intestinal mucus secretion and increased intestinal permeability. Moreover, PVC-MPs exposure decreased mRNA expression levels of colonic mucus secretion-related genes, indicating dysfunction of intestinal mucus secretion after exposure to PVC-MPs. With regard to the gut microbiota, high throughput sequencing of the full-length 16S rRNA gene sequencing indicated 15 and 17 kinds of gut microbes changed markedly after PVC-MPs exposure at the genus and species level, respectively. Furthermore, marked alterations in the gut microbiome and fecal metabolic profiles were observed, most of which were related to intestinal injury and barrier dysfunction. These results show that exposure to PVC-MPs leads to intestinal injury and changes gut microbiome composition and metabolome profiles, thus the health risk of PVC-MPs to animals needs more concern. This study helps to provide a new idea about the health risk of PVC-MPs to humans.

Traumatic axonal injury: neuropathological features, postmortem diagnostic methods, and strategies.

Traumatic brain injury (TBI) has high morbidity and poor prognosis and imposes a serious socioeconomic burden. Traumatic axonal injury (TAI), which is one of the common pathological changes in the primary injury of TBI, is often caused by the external force to the head that causes the white matter bundles to generate shear stress and tension; resulting in tissue damage and leading to the cytoskeletal disorder. At present, the forensic pathological diagnosis of TAI-caused death is still a difficult problem. Most of the TAI biomarkers studied are used for the prediction, evaluation, and prognosis of TAI in the living state. The research subjects are mainly humans in the living state or model animals, which are not suitable for the postmortem diagnosis of TAI. In addition, there is still a lack of recognized indicators for the autopsy pathological diagnosis of TAI. Different diagnostic methods and markers have their limitations, and there is a lack of systematic research and summary of autopsy diagnostic markers of TAI. Therefore, this study mainly summarizes the pathological mechanism, common methods, techniques of postmortem diagnosis, and corresponding biomarkers of TAI, and puts forward the strategies for postmortem diagnosis of TAI for forensic cases with different survival times, which is of great significance to forensic pathological diagnosis.

Regulating Valence States of Gold Nanocluster as a New Strategy for the Ultrasensitive Electrochemiluminescence Detection of Kanamycin.

Monitoring of kanamycin residue has attracted considerable attention owing to the potential harm caused by the abuse of kanamycin. However, the detection of kanamycin has been limited owing to its electrochemical and optical inertness. Herein, we report a facile and highly efficient electrochemiluminescence (ECL) strategy for the detection of kanamycin based on the valence state effect of gold nanocluster (AuNC) probes. It is proven that Au0 in chemically reduced AuNCs (CR-AuNCs) could be oxidized to AuI via the redox reaction between kanamycin and CR-AuNCs in the presence of H2O2, resulting in ECL quenching due to the valence state change of CR-AuNCs. Because the ECL of the AuNC probes is sensitively affected by the valence state, excellent sensitivity for kanamycin was achieved without any signal amplification operation and aptamers. A preferable linear-dependent curve was acquired in the detection range from 1.0 × 10-11 to 3.3 × 10-5 M with an extremely low detection limit of 1.5 × 10-12 M. The proposed kanamycin sensing platform is very simple and shows high selectivity and an extremely broad linear range detection of kanamycin. Furthermore, the proposed sensing platform can detect kanamycin in milk samples with excellent recoveries. Therefore, this sensing strategy provides an effective and facile way to detect kanamycin and can help promote the understanding of the constructed mechanism of the AuNC-based ECL system, thus greatly broadening its potential application in ECL fields.

Highly Conductive Ligand-Free Cs2 PtBr6 Perovskite Nanocrystals with a Narrow Bandgap and Efficient Photoelectrochemical Performance.

Design of high-performance all-inorganic halide perovskites, especially lead-free perovskites, is key to the broadening of its application prospects. Herein, the authors report the synthesis of ligand-free cesium platinum (IV) bromide nanocrystals (Cs2 PtBr6 NCs), a new kind of vacancy-ordered lead-free perovskite nanomaterial, by a facile one-pot method. The Cs2 PtBr6 NCs exhibits a narrow band gap of 1.32 eV covering the entire visible range, which is supported by density functional theory calculations. Together with their high conductivity, matching energy levels with the work function of carbon electrodes, and excellent environmental stability, this NC displays a cathodic photocurrent density as high as 335 µA cm-2 , two orders of magnitude higher than other perovskites in aqueous solutions without the need of other electron acceptors. These combined properties suggest that the Cs2 PtBr6 NCs have great potentials in a wide range of photoelectronic and photoelectrochemical sensing applications.

Construction of a Stable Expression Cell Line of Human Phospholamban. / 人源性受磷蛋白稳定表达细胞系的构建.

OBJECTIVES: To construct a cell line that can stably express human phospholamban(PLN) and initially explore its application in the study of myocardial toxicity mechanism. METHODS: FastCloning method was used to insert the open reading frame sequence of target gene PLN into eukaryotic expression vector pcDNA5/FRT/TO(hereinafter referred to as pDFT) to construct the pDFT-PLN-Flag plasmid. The Flp-InTM T-RExTM 293 cells were generated by cotransfection of the constructed plasmid and pOG44 plasmid to express the target gene. Successfully recombined monoclonal cell lines were screened by hygromycin B resistance. Western blot and indirect immunofluorescence (IFA) were used to examine the expression of the target protein in recombinant cells. After the cell line was exposed to aconitine, it was verified by Western blot to detect changes in PLN protein phosphorylation. RESULTS: After PCR amplification of the recombinant plasmid and DNA electrophoresis, the length of the amplified product is the same as the known PLN gene fragment, which is consistent with the open reading frame (ORF) sequence of the human PLN gene after sequencing. IFA and Western blot showed that the constructed proliferation cell line can stably express high levels of human PLN under induction and regulation. Preliminary results showed that the phosphorylation level of Thr17-PLN decreased after two hours of exposure to 1 µmol/L aconitine. CONCLUSIONS: This human cell line can stably express PLN and can be used to study the mechanism of action of aconitine on the cell at molecular level.

Mechanistic Insight into a Novel Ultrasensitive Nicotine Assay Base on High-Efficiency Quenching of Gold Nanocluster Cathodic Electrochemiluminescence.

Monitoring nicotine concentrations in human fluids is extremely crucial owing to the harmful effect of nicotine on human health. Herein, it is shown that nicotine could quench the cathodic electrochemiluminescence (ECL) of gold nanoclusters (AuNCs) with high efficiency. The ECL quenching mechanism of nicotine was studied in detail using various experimental tools and theoretical calculations. It was concluded that the strongly oxidizing intermediate SO4•-, produced from K2S2O8, could oxidized nicotine, resulting in ECL emission quenching. On the basis of this high-efficiency ECL quenching of the AuNCs/K2S2O8 system, a recyclable, ultrasensitive, and selective ECL sensing platform for nicotine detection was proposed. Even in the absence of any complex signal amplification techniques, the ECL sensor for nicotine detection showed an unprecedentedly low detection limit of 7.0 × 10-13 M (S/N = 3) and a wide linear range over 8 orders of magnitude. Most remarkably, it could be successfully used for nicotine detection in human urine samples. This is expected to promote the investigations and applications on nicotine-related diseases. We believe that the proposed ECL platform can hold great prospects for commercialization in biomedical fields and tobacco industries.

Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.

Electrochemiluminescent immunoassay for the lung cancer biomarker CYFRA21-1 using MoOx quantum dots.

Molybdenum oxide quantum dots (MoOx QDs) were synthesized by a one-pot method and used as a versatile probe in an electrochemiluminescent (ECL) immunoassay of the non-small cell lung cancer biomarker cytokeratin 19 fragment 21-1 (CYFRA21-1) as a model analyte. The MoOx QDs exhibited stable and strong cathodic green ECL, with an emission peak at 535 nm, in the presence of K2S2O8 within the potential range of -2.0 to 0 V. On exposure to CYFRA21-1, the ECL decreases because of the immunoreaction between CYFRA21-1 and its antibody which generates a barrier for electron transfer. The determination of CYFRA21-1 with favorable analytical performances was successfully realized under the optimal conditions. ECL decreases linearly in the 1 pg mL-1 to 350 ng mL-1 CYFRA21-1 concentration range, and the detection is as low as 0.3 pg mL-1. Excellent recoveries from CYFRA21-1-spiked human serum indicate that the assay can be operated under physiological conditions. Graphical abstractSchematic representation of the fabrication of molybdenum oxide quantum dots (MoOx QDs) and the electrochemiluminescent (ECL) immunoassay based on the use of the MoOx QDs ECL probe for cytokeratin 19 fragment 21-1 (CYFRA21-1).