PRMD: an integrated database for plant RNA modifications.

The scope and function of RNA modifications in model plant systems have been extensively studied, resulting in the identification of an increasing number of novel RNA modifications in recent years. Researchers have gradually revealed that RNA modifications, especially N6-methyladenosine (m6A), which is one of the most abundant and commonly studied RNA modifications in plants, have important roles in physiological and pathological processes. These modifications alter the structure of RNA, which affects its molecular complementarity and binding to specific proteins, thereby resulting in various of physiological effects. The increasing interest in plant RNA modifications has necessitated research into RNA modifications and associated datasets. However, there is a lack of a convenient and integrated database with comprehensive annotations and intuitive visualization of plant RNA modifications. Here, we developed the Plant RNA Modification Database (PRMD; http://bioinformatics.sc.cn/PRMD and http://rnainformatics.org.cn/PRMD) to facilitate RNA modification research. This database contains information regarding 20 plant species and provides an intuitive interface for displaying information. Moreover, PRMD offers multiple tools, including RMlevelDiff, RMplantVar, RNAmodNet and Blast (for functional analyses), and mRNAbrowse, RNAlollipop, JBrowse and Integrative Genomics Viewer (for displaying data). Furthermore, PRMD is freely available, making it useful for the rapid development and promotion of research on plant RNA modifications.

A mineral-based origin of Earth's initial hydrogen peroxide and molecular oxygen.

Terrestrial reactive oxygen species (ROS) may have played a central role in the formation of oxic environments and evolution of early life. The abiotic origin of ROS on the Archean Earth has been heavily studied, and ROS are conventionally thought to have originated from H2O/CO2 dissociation. Here, we report experiments that lead to a mineral-based source of oxygen, rather than water alone. The mechanism involves ROS generation at abraded mineral-water interfaces in various geodynamic processes (e.g., water currents and earthquakes) which are active where free electrons are created via open-shell electrons and point defects, high pressure, water/ice interactions, and combinations of these processes. The experiments reported here show that quartz or silicate minerals may produce reactive oxygen-containing sites (≡SiO•, ≡SiOO•) that initially emerge in cleaving Si-O bonds in silicates and generate ROS during contact with water. Experimental isotope-labeling experiments show that the hydroxylation of the peroxy radical (≡SiOO•) is the predominant pathway for H2O2 generation. This heterogeneous ROS production chemistry allows the transfer of oxygen atoms between water and rocks and alters their isotopic compositions. This process may be pervasive in the natural environment, and mineral-based production of H2O2 and accompanying O2 could occur on Earth and potentially on other terrestrial planets, providing initial oxidants and free oxygen, and be a component in the evolution of life and planetary habitability.

Ionizing radiation induces neurotoxicity in Xenopus laevis embryos through neuroactive ligand-receptor interaction pathway.

Ionizing radiation (IR) poses a significant threat to both the natural environment and biological health. Exposure to specific doses of ionizing radiation early in an organism's development can lead to developmental toxicity, particularly neurotoxicity. Through experimentation with Xenopus laevis (X. laevis), we examined the effects of radiation on early developmental stage. Our findings revealed that radiation led to developmental abnormalities and mortality in X. laevis embryos in a dose-dependent manner, disrupting redox homeostasis and inducing cell apoptosis. Additionally, radiation caused neurotoxic effects, resulting in abnormal behavior and neuron damage in the embryos. Further investigation into the underlying mechanisms of radiation-induced neurotoxicity indicated the potential involvement of the neuroactive ligand-receptor interaction pathway, which was supported by RNA-Seq analysis. Validation of gene expression associated with this pathway and analysis of neurotransmitter levels confirmed our hypothesis. In addition, we further validated the important role of this signaling pathway in radiation-induced neurotoxicity through edaravone rescue experiments. This research establishes a valuable model for radiation damage studying and provides some insight into radiation-induced neurotoxicity mechanisms.

Bazedoxifene analogs as potential WDHD1 degraders and antitumor agents: Synthesis, evaluation and molecular dynamics simulation studies.

DNA repair is strongly associated with tumor resistance to radiotherapy and chemotherapy. WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a key adaptor for homologous recombination repair of DNA, and its overexpression is relevant to the poor prognosis of many tumor patients. We previously have identified and validated bazedoxifene (BZA), which had 60% inhibitory rate on WDHD1 in MCF7 cells at 10 µM, from the Food and Drug Administration-approved compound library. Here, we initially established the binding model of BZA, synthesized and evaluated eight BZA analogs. Further, we detailed the use of molecular dynamics simulations to provide insights into the basis for activity against WDHD1. This binding mode will be instructive for the development of new WDHD1 degraders.

PET imaging of new target CDK19 in prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) is a superior method to predict patients' risk of cancer progression and response to specific therapies. However, its performance is limited for neuroendocrine prostate cancer (NEPC) and PSMA-low prostate cancer cells, resulting in diagnostic blind spots. Hence, identifying novel specific targets is our aim for diagnosing those prostate cancers with low PSMA expression. METHODS: The Cancer Genome Atlas (TCGA) database and our cohorts from men with biopsy-proven high-risk metastatic prostate cancer were used to identify CDK19 and PSMA expression. PDX lines neP-09 and P-16 primary cells were used for cellular uptake and imaging mass cytometry in vitro. To evaluate in vivo CDK19-specific uptake of gallium(Ga)-68-IRM-015-DOTA, xenograft mice models and blocking assays were used. PET/CT imaging data were obtained to estimate the absorbed dose in organs. RESULTS: Our study group had reported the overexpression of a novel tissue-specific gene CDK19 in high-risk metastatic prostate cancer and CDK19 expression correlated with metastatic status and tumor staging, independently with PSMA and PSA levels. Following up on this new candidate for use in diagnostics, small molecules targeting CDK19 labeled with Ga-68 (68Ga-IRM-015-DOTA) were used for PET in this study. We found that the 68Ga-IRM-015-DOTA was specificity for prostate cancer cells, but the other cancer cells also took up little 68Ga-IRM-015-DOTA. Importantly, mouse imaging data showed that the NEPC and CRPC xenografts exhibited similar signal strength with 68Ga-IRM-015-DOTA, but 68Ga-PSMA-11 only stained the CRPC xenografts. Furthermore, target specificity was elucidated by a blocking experiment on a CDK19-bearing tumor xenograft. These data concluded that 68Ga-CDK19 PET/CT was an effective technology to detect lesions with or without PSMA in vitro, in vivo, and in the PDX model. CONCLUSION: Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that 68Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.

Laparoscopic hiatal hernia repair for treating patients with massive hiatal hernia and iron-deficiency anaemia.

BACKGROUND: Massive hiatal hernias may result in extraoesophageal symptoms, including iron-deficiency anaemia. However, the role played by hiatal hernias in iron-deficiency anaemia is not clearly understood. We examined the prevalence of anaemia in patients with massive hiatal hernias and the frequency of anaemia resolution after laparoscopic hiatal hernia repair at long term follow-up. METHODS: Patients who underwent laparoscopic hiatal hernia repair from June 2008 to June 2019 were enrolled in this study. We collected the patients' demographic and clinical data from their medical records, and compared the pre-surgical and post-surgical findings (at 1 week and 3 months post-surgery). All patients with adequate documentation underwent post-surgical follow-up to evaluate improvements in clinical symptoms and signs. RESULTS: A total of 126 patients with massive hiatal hernias underwent laparoscopic hiatal hernia repair. Of these, 35 (27.8%) had iron-deficiency anaemia. Anaemia was resolution in all the patients and they had significantly reduced GERD-Q scores at 3 months postoperatively (P<0.01) .The mean follow-up period was 60 months. Iron-deficiency anaemia resolution after hiatal hernia repair was achieved in 93.9% of the patients. CONCLUSION: Anaemia is common in patients with massive hiatal hernias, and most of our patients were symptomatic because of their anaemia. Moreover, in patients with massive hiatal hernias, iron-deficiency anaemia resolution is likely after laparoscopic hiatal hernia repair.

[Research progress in prevention and treatment of radiation-induced intestinal injury by traditional Chinese medicine active components].

Radiation-induced intestinal injury(RIII), a common complication of radiotherapy for pelvic malignancies, affects the quality of life and the radiotherapy efficacy for cancer. Currently, the main clinical approaches for the prevention and treatment of RIII include drug therapy, hyperbaric oxygen therapy, and surgical treatment. Among these methods, drug therapy is cost-effective. Traditional Chinese medicine(TCM) containing a variety of active components demonstrates mild side effects and good efficacy in preventing and treating RIII. Studies have proven that TCM active components, such as flavonoids, terpenoids, phenylpropanoids, and alkaloids, can protect the intestine against RIII by inhibiting oxidative stress, regulating the expression of inflammatory cytokines, modulating the mitochondrial apoptosis pathway, adjusting intestinal flora, and suppressing cell apoptosis. These mechanisms can help alleviate the symptoms of RIII. The paper aims to provide a theoretical reference for the discovery of new drugs for the prevention and treatment of RIII by reviewing the literature on TCM active components in the last 10 years.

Caloric restriction alleviates radiation injuries in a sex-dependent fashion.

Safe and effective regimens are still needed given the risk of radiation toxicity from iatrogenic irradiation. The gut microbiota plays an important role in radiation damage. Diet has emerged as a key determinant of the intestinal microbiome signature and function. In this report, we investigated whether a 30% caloric restriction (CR) diet may ameliorate radiation enteritis and hematopoietic toxicity. Experimental mice were either fed ad libitum (AL) or subjected to CR preconditioning for 10 days and then exposed to total body irradiation (TBI) or total abdominal irradiation (TAI). Gross examinations showed that short-term CR pretreatment restored hematogenic organs and improved the intestinal architecture in both male and female mice. Intriguingly, CR preconditioning mitigated radiation-induced systemic and enteric inflammation in female mice, while gut barrier function improved in irradiated males. 16S rRNA high-throughput sequencing showed that the frequency of pro-inflammatory microbes, including Helicobacter and Desulfovibrionaceae, was reduced in female mice after 10 days of CR preconditioning, while an enrichment of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibaculum, Clostridiales, and Lactobacillus, was observed in males. Using fecal microbiota transplantation (FMT) or antibiotic administration to alter the gut microbiota counteracted the short-term CR-elicited radiation tolerance of both male and female mice, further indicating that the radioprotection of a 30% CR diet depends on altering the gut microbiota. Together, our findings provide new insights into CR in clinical applications and indicate that a short-term CR diet prior to radiation modulates sex-specific gut microbiota configurations, protecting male and female mice against the side effects caused by radiation challenge.

Discovery of Natural Ursane-type SENP1 Inhibitors and the Platinum Resistance Reversal Activity Against Human Ovarian Cancer Cells: A Structure-Activity Relationship Study.

Platinum-resistant ovarian cancer is one of the most common and refractory gynecologic cancers around the world. The SENP1/JAK2 (small ubiquitin-like modifier-specific protease 1/Janus activating kinase 2) axis activation has been proposed as a critical mechanism in platinum-resistant ovarian cancer, and as such, SENP1 inhibitors become a feasible alternative to reverse platinum resistance. In this work, 29 commercially available natural ursane-type aglycones were tested for their SENP1 inhibitory activities, among which 12 aglycones showed IC50 activity at the concentration below 5 µM. Pomolic acid and tormentic acid were identified as potent SENP1 inhibitors with the IC50 values of 5.1 and 4.3 µM, respectively. The structure-activity relationship (SAR) of ursane-type SENP1 inhibitors was evaluated. A molecular docking model of the SENP1-tormentic acid complex was obtained and applied to describe the SAR. Moreover, the combinations of cisplatin with pomolic acid (IC50 = 3.69 µM, combination index (CI) = 0.23) and tormentic acid (IC50 = 2.40 µM, CI = 0.30) exhibited potent platinum-resistant reversal activities to cisplatin only (IC50 = 28.23 µM) against the human ovarian cancer SKOV3 cells. The data suggested a potential for pomolic acid and tormentic acid to be promising compounds for in vivo studies of platinum-resistant ovarian cancer with SENP1 activation.

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors.

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays in vitro. Among them, compounds H34, H42, H48, and H52 displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays in vitro and in vivo proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound H52 exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTSStructural fusion was used to screen brain penetrating PARP-1 inhibitors.55 benzodiazepines were evaluated for their PARP-1 inhibition activity.Four compounds displayed acceptable inhibition effects on breast cancer cells.The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.

Microbiome characteristics and the key biochemical reactions identified on stone world cultural heritage under different climate conditions.

The surfaces of historical stone monuments are visibly covered with a layer of colonizing microorganisms and their degradation products. In this study, a metadata analysis was conducted using the microbial sequencing data available from NCBI database to determine the diversity, biodeterioration potential and functionality of the stone microbiome on important world cultural heritage sites under four different climatic conditions. The retrieved stone microbial community composition in these metagenomes shows a clear association between climate types of the historical monuments and the diversity and taxonomic composition of the stone microbiomes. Shannon diversity values showed that microbial communities on stone monuments exposed to dry climate were more diverse than those under humid ones. In particular, functions associated with photosynthesis and UV resistance were identified from geographical locations under different climate types. The distribution of key microbial determinants responsible for stone deterioration was linked to survival under extreme environmental conditions and biochemical capabilities and reactions. Among them, biochemical reactions of the microbial nitrogen and sulfur cycles were most predominant. These stone-dwelling microbiomes on historical stone monuments were highly diverse and self-sustaining driven by energy metabolism and biomass accumulation. And metabolic products of the internal geomicrobiological nitrogen cycling on these ancient monuments play a unique role in the biodeterioration of stone monuments. These results highlight the significance of identifying the essential microbial biochemical reactions to advance the understanding of stone biodeterioration for protection management.

Discovery of novel triazole compounds as selective IL-1ß releasement inhibitors.

Inflammation and immunity are closely related to the occurrence and development of a variety of immune diseases. Although IL-1ß has been identified as a key cytokine in many immune diseases, safe and specific small molecular IL-1ß releasement inhibitors are still scarce and urgently required in clinic. The investigation prospect of triazoleis limited by its complicated pharmacological effect which exhibited inferior effects on IL-1ß and TNF-α. Herein, 36 novel derivatives were designed and synthesized, and nearly half of the derivatives exhibited much better selectivity on IL-1ß releasement inhibition as well as keep similar inhibitory activities to lead compound. In 20 µM, compound 19 exhibited IL-1ß releasement inhibitory activity (IC50 = 5.489 µM) which closed to the original compound, and 4.5-fold superior selectivity (SI = 4.71) to the lead compound (SI = 0.82). A probable SAR model of triazole derivatives for IL-1ß releasement inhibition and selectivity was also proposed, which might promote the discovery of more effective and specific IL-1ß releasement inhibitors in the future.

V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as a prognostic biomarker of poor outcomes in esophageal cancer patients.

BACKGROUND: Esophageal cancer is one of the most aggressive malignancies, and is associated with multiple genetic mutations. At present, the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation has been observed in esophageal cancer and is associated with poor prognosis. This study aimed to investigate the protein expression of BRAF in esophageal cancer and determine its effect on patient outcomes. METHODS: We used immunohistochemistry to detect the expression of BRAF via tissue microarrays in esophageal cancer samples, the Kaplan-Meier method to perform survival analysis, and the Cox proportional hazards regression model to explore the risk factors of esophageal cancer. The role of BRAF in the proliferation, invasion, and metastasis of esophageal cancer was studied by clone formation, scratch test, Transwell invasion and migration test. The tumor-bearing model of BRAF inhibitor was established using TE-1 cells, and corresponding negative control was set up to observe the growth rate of the two models. RESULTS: The results revealed that BRAF overexpression was significantly correlated with Ki67 (P < 0.05). Survival analysis showed that BRAF overexpression contributed to a shorter overall survival (P = 0.014) in patients with esophageal cancer. Univariate and multivariate regression analyses demonstrated that BRAF was a prognostic factor for poor esophageal cancer outcomes (P < 0.05). Small interfering RNA knockdown of BRAF significantly reduced the cell clone formation rate compared to the control group. Transwell assay analysis showed that the migration and invasion of cells in the experimental group were significantly inhibited relative to the control group, and the inhibition rates of the small interfering RNA group were 67% and 60%, respectively. In the scratch test, the wound healing ability of the BRAF knockdown group was significantly weaker than that of the control group. There were significant differences in tumor growth volume and weight between the two groups in nude mice. CONCLUSION: BRAF overexpression may serve as an effective predictive factor for poor prognosis.

Functionalized nanoparticles with monocyte membranes and rapamycin achieve synergistic chemoimmunotherapy for reperfusion-induced injury in ischemic stroke.

BACKGROUND: Ischemic stroke is an acute and severe neurological disease, and reperfusion is an effective way to reverse brain damage after stroke. However, reperfusion causes secondary tissue damage induced by inflammatory responses, called ischemia/reperfusion (I/R) injury. Current therapeutic strategies that control inflammation to treat I/R are less than satisfactory. RESULTS: We report a kind of shield and sword nano-soldier functionalized nanoparticles (monocyte membranes-coated rapamycin nanoparticles, McM/RNPs) that can reduce inflammation and relieve I/R injury by blocking monocyte infiltration and inhibiting microglia proliferation. The fabricated McM/RNPs can actively target and bind to inflammatory endothelial cells, which inhibit the adhesion of monocytes to the endothelium, thus acting as a shield. Subsequently, McM/RNPs can penetrate the endothelium to reach the injury site, similar to a sword, and release the RAP drug to inhibit the proliferation of inflammatory cells. In a rat I/R injury model, McM/RNPs exhibited improved active homing to I/R injury areas and greatly ameliorated neuroscores and infarct volume. Importantly, in vivo animal studies revealed good safety for McM/RNPs treatment. CONCLUSION: The results demonstrated that the developed McM/RNPs may serve as an effective and safe nanovehicles for I/R injury therapy.

Microbiome and nitrate removal processes by microorganisms on the ancient Preah Vihear temple of Cambodia revealed by metagenomics and N-15 isotope analyses.

Preah Vihear temple is one of the most significant representatives of the ancient Angkorian temples listed as United Nations Educational, Scientific and Cultural Organization (UNESCO) World Heritage Sites. The surfaces of this Angkor sandstone monument are covered with deteriorated materials, broadly called "sediments" here, resulting from a long time of weathering of the sandstone. The sediments might adversely affect the ancient sandstone substratum of this cultural heritage, and the potential risk from them is essential information for current strategies and on-going protection and management. The extracted DNA from the sediment samples of this temple was used for Illumina high-throughput sequencing analysis, resulting in approximately 12 Gb of metagenomic dataset. The results of this shotgun metagenomic analysis provided a thorough information of the phylogenetic groups presented in the microbiome of the sediment samples, indicating that potential metabolic activities, involving different geomicrobiological cycles, may occur in this microbiome. The phylogenetic result revealed that the majority of metagenomic reads were affiliated with Proteobacteria, Acidobacteria, Actinobacteria, and Bacteroidetes at the phylum level. The metabolic reconstruction results indicated that the important geomicrobiological cycling processes include carbon sequestration, and nitrogen and sulfur transformation as the potentially active ones in the sediments of the sampling sites. Specifically, the dissimilatory nitrate reduction to ammonium (DNRA) and the newly discovered complete ammonia oxidation (comammox) were retrieved from this metagenomic dataset. Furthermore, the genetic information on the presence of acid-producing processes by sulfur- and ammonia-oxidizing bacteria and archaea in this metagenomic dataset suggested that the microbial flora in these samples has the potential to participate in the degradation of sandstone cultural heritage by producing acids. N-15 isotope amendment and incubation analysis results confirmed the presence of active denitrification, but not anammox activity at this temple. These results are important for our knowledge on the microbial community composition and microbial biodeterioration processes affecting this sandstone cultural heritage and will aid in the protection and management of the ancient Preah Vihear temple.Key Points• Microbiota on Preah Viher temple was analyzed using NGS.• Nitrate-N transformation by DNRA, comammox, and denitrifcation was detected.• N-15 isotope analysis confirmed the active denitrifcation, but not Anammox.• Accumulation of nitrate is a result of less active removal by denitrification.

Correction to: Microbiome and nitrate removal processes by microorganisms on the ancient Preah Vihear temple of Cambodia revealed by metagenomics and N-15 isotope analyses.

The published online version contains mistake for the author the authors correction to change the name from Clara Uriz to Clara Urzì was missed.

Ursolic acid derivative UA232 evokes apoptosis of lung cancer cells induced by endoplasmic reticulum stress.

CONTEXT: Ursolic acid (UA), a natural product, shows a broad spectrum of anticancer effects. However, the poor bioavailability and efficacy of UA limit its clinical application. OBJECTIVE: We developed novel analogues of UA with enhanced antitumor activities by the extensive chemical modification of UA. MATERIALS AND METHODS: We developed multiple compounds by structural modification of UA, and found that UA232 had stronger activity than UA. The effects of UA232 (0-50 µM) on inhibiting the proliferation of A549 and H460 cells were determined by CCK-8 for 24, 48, or 72 h. The proapoptotic effect of UA232 was analyzed by microscopy and flow cytometry, and the potential signal pathway affected by UA232 was further validated by Western blotting and flow cytometry. RESULTS: Compared with UA, UA232 showed a stronger ability to inhibit the proliferation of lung cancer cells (IC50 = 5.4-6.1 µM for A549 and 3.9-5.7 µM for H460 cells). UA232 could induce not only cell cycle arrest in the G0/G1 phase but also apoptosis in both A549 and H460 cells. The treatment of UA232 could lead to an increase of CHOP expression rather than an increase in Bax or caspase-8, indicating that the apoptosis induced by UA232 was correlated with the endoplasmic reticulum stress (ER stress) pathway. Treatment with the ER stress-specific inhibitor, 4-PBA, decreased the ability of UA232 to induce apoptosis in A549 and H460 cells. CONCLUSION: UA232 induced apoptosis through the ER stress pathway, and showed stronger growth-inhibitory effects in A549 and H460 cells compared to UA, which may be a potential anticancer drug to suppress the proliferation of lung cancer.

Single-Particle Enumeration-Based Sensitive Glutathione S-Transferase Assay with Fluorescent Conjugated Polymer Nanoparticle.

Glutathione S-transferase (GST) is a group of multifunctional enzyme and participates in many physiological processes, such as xenobiotic biotransformation, drug metabolism, and degradation of toxic products. Herein, we demonstrate a label-free fluorescent conjugated polymer nanoparticle (FCPNPs)-based single-particle enumeration (SPE) method for the sensitive GST assay. Fluorescence resonance energy transfer (FRET) is formed between the glutathione-modified FCPNPs (FCPNPs-GSH) and polyethylenimine-capped gold nanoparticles (GNPs@PEI). Therefore, the fluorescence of FCPNPs-GSH is quenched remarkably. In the presence of GST, GNPs@PEI stay away from FCPNPs-GSH due to the specific interaction between FCPNPs-GSH and GST, leading to the inhibition of FRET. As a result, the fluorescence emission of FCPNPs-GSH is restored, which is reflected as the increase of the number of fluorescent particles in the microscopic image. By statistically counting the target concentration-dependent fluorescent particle number, accurate quantification of GST is achieved. The linear range from 0.01 to 6 µg/mL is obtained for GST assay and the limit-of-detection (LOD) is 1.03 ng/mL, which is much lower than the ensemble fluorescence spectra measurements in bulk solution. In urine sample assay, satisfactory recoveries in the range of 97.5-106.5.0% are achieved. Because of the high sensitivity and excellent specificity, this method can be extended to the detection of other disease-related biomolecules in the future.

Efficient Modulation of ß-Amyloid Peptide Fibrillation with Polymer Nanoparticles Revealed by Super-Resolution Optical Microscopy.

ß-Amyloid peptide (Aß) aggregation is the essential hallmark of neurodegenerative disorders such as Alzheimer's disease. Efficient inhibitors are highly desired for the prevention of Aß assembly that has been considered as the primary therapeutic strategy for neurodegenerative diseases. Apart from this, visualization of the aggregates and morphology at high spatial resolution is widely considered of crucial significance on biological treatment. In this work, we have developed small-sized (with diameter of ∼4.7 nm) and positively charged fluorescent conjugated polymer nanoparticles (CPNPs) with strong inhibition effect on Aß1-40 peptides fibrillation. Interestingly, the CPNPs also possess excellent photophysical properties, including high photon counts, robust blinking, and repetitive fluorescence switching, that are especially suitable for localization-based super-resolution imaging. Spatial resolution of ∼20 nm for these blinking CPNPs is readily achieved. According to the optical microscopic results, it was found that binding of CPNPs to the terminal of seed fibrils can effectively inhibit the fibrillation process. Owing to these attractive biological and unique photophysical properties, the small-sized CPNPs show high potential in a variety of super-resolution based biological applications.

Single-Particle Enzyme Activity Assay with Spectral-Resolved Dark-Field Optical Microscopy.

In a clinical assay, enzymes are essential biomarkers for human disease diagnosis. In this work, a spectral-resolved single-particle detection (SPD) method is introduced to quantify alkaline phosphatase (ALP) activity in human serum with a supraparticle (SP) based on MnO2-modified gold nanoparticle (denoted as GNP@MnO2 SP) as the probe. In the presence of ALP, 2-phospho-l-ascorbic acid trisodium salt can be hydrolyzed into l-ascorbic acid, which serves as a good reduction agent to trigger the decomposition of the MnO2 shell on the GNP surface. Given that a trace amount of ALP exists, noticeable scattering color change can be detected at the single-particle level due to the sensitive localized surface plasmon resonance (LSPR) effect from GNPs. With spectral-resolved dark-field optical microscopy, a linear dynamic range of 0.06 to 2.48 mU/mL ( R2 = 0.99) and a very low limit of detection of 5.8 µU/mL for the ALP assay are readily achieved, which is more sensitive over the methods based on ensemble sample measurement. As a consequence, this strategy opens a new avenue for the design of an ultrasensitive detection method for disease-correlated biomarker diagnosis in the future.