DNA polymerase epsilon binds histone H3.1-H4 and recruits MORC1 to mediate meiotic heterochromatin condensation.

Heterochromatin is essential for genomic integrity and stability in eukaryotes. The mechanisms that regulate meiotic heterochromatin formation remain largely undefined. Here, we show that the catalytic subunit (POL2A) of Arabidopsis DNA polymerase epsilon (POL ε) is required for proper formation of meiotic heterochromatin. The POL2A N terminus interacts with the GHKL adenosine triphosphatase (ATPase) MORC1 (Microrchidia 1), and POL2A is required for MORC1's localization on meiotic heterochromatin. Mutations affecting the POL2A N terminus cause aberrant morphology of meiotic heterochromatin, which is also observed in morc1. Moreover, the POL2A C-terminal zinc finger domain (ZF1) specifically binds to histone H3.1-H4 dimer or tetramer and is important for meiotic heterochromatin condensation. Interestingly, we also found similar H3.1-binding specificity for the mouse counterpart. Together, our results show that two distinct domains of POL2A, ZF1 and N terminus bind H3.1-H4 and recruit MORC1, respectively, to induce a continuous process of meiotic heterochromatin organization. These activities expand the functional repertoire of POL ε beyond its classic role in DNA replication and appear to be conserved in animals and plants.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Corrosion and Interfacial Contact Resistance of NiTi Alloy as a Promising Bipolar Plate for PEMFC.

Titanium (Ti) is generally considered as an ideal bipolar plate (BPP) material because of its excellent corrosion resistance, good machinability and lightweight nature. However, the easy-passivation property, which leads to increased interfacial contact resistance (ICR) and subsequently decreased cell performance, limits its large-scale commercial application in proton exchange membrane fuel cells (PEMFCs). In this paper, we proposed a NiTi alloy prepared by suction casting as a promising bipolar plate for PEMFCs. This NiTi alloy exhibits significantly decreased ICR values (16.8 mΩ cm2 at 1.4 MPa) compared with pure Ti (88.6 mΩ cm2 at 1.4 MPa), along with enhanced corrosion resistance compared with pure nickel (Ni). The superior corrosion resistance of NiTi alloy is accredited to the nobler open circuit potential and corrosion potential, coupled with low corrosion current densities and passive current densities. The improved ICR can be interpreted by the existence of high-proportioned metallic Ni in the passive film, which contributes to the reduced capacitance characteristic of the passive film (compared with Ti) and enhances charge conduction. This work provides a feasible option to ameliorate BPP material that may have desirable corrosion resistance and ICR.

Sensitive NIR Fluorescence Identification of Bacteria in Whole Blood with Bioorthogonal Nanoprobes for Early Sepsis Diagnosis.

Sepsis is one of the leading causes of death worldwide. The disease progression of sepsis is very fast, and there is a 7-9% increase in mortality every hour. Therefore, rapid and sensitive detection of pathogenic bacteria is crucial for the timely treatment of sepsis as well as the reduction of mortality. Herein, we present a sensitive near-infrared (NIR) fluorescence identification and a rapid magnetic capture based on bioorthogonal nanoprobes for the detection of multiple bacteria in whole blood. The nanoprobes with NIR fluorescence/magnetic properties were modified with dibenzocyclooctyne groups and used to capture and recognize the bacteria via bioorthogonal reaction. The magnetic nanoprobes showed superparamagnetic properties with a saturation magnetization as high as 63 emu/g. Through clicking with the azide groups inserted on the bacteria walls by metabolic engineering, the bioorthogonal magnetic nanoprobes allow fast and broad-spectrum capture of both Gram-positive and Gram-negative bacteria. The bioorthogonal NIR fluorescent nanoprobes with a maximum emission at 900 nm can effectively avoid background interference, further enabling sensitive identification of the bacteria in whole blood. The detection limit was as low as 4 CFU/mL in less than 2.5 h and the nanoprobes were successfully applied to the detection of bacteria in blood samples from the patients with sepsis, showing the potential application in early sepsis diagnosis and clinical studies.

Telemedicine and Clinical Outcomes in Peritoneal Dialysis: A Propensity-Matched Study.

INTRODUCTION: Telemedicine (TM) has shown to provide potential benefits on clinical outcomes in patients with chronic kidney disease but limited evidences published in the peritoneal dialysis (PD) population. This study aimed to explore the long-term effects of TM on the mortality and technique failure. METHODS: The Peritoneal Dialysis Telemedicine-assisted Platform Cohort Study (PDTAP Study) was conducted prospectively in 27 hospitals in China since 2016. Patient and practice data were collected through the doctor-end of the TM app (Manburs) for all participants. TM including self-monitoring records, on-line education materials, and real-time physician-patient contact was only performed for the patient-end users of the Manburs. The primary outcome was all-cause mortality. The secondary outcomes were cause-specific mortality and all-cause and cause-specific permanent transfer to hemodialysis. RESULTS: A total of 7,539 PD patients were enrolled between June 2016 and April 2019, with follow-up till December 2020. Patients were divided into two cohorts: TM group (39.1%) and non-TM group (60.9%). A propensity score was used to create 2,160 matched pairs in which the baseline covariates were well-balanced. There were significantly lower risks of all-cause mortality (HR 0.59 [0.51, 0.67], p < 0.001), CVD mortality (HR 0.59 [0.49, 0.70], p < 0.001), all-cause transfer to hemodialysis (0.57 [0.48, 0.67], p < 0.001), transfer to hemodialysis from PD-related infection (0.67 [0.51, 0.88], p = 0.003), severe fluid overload (0.40 [0.30, 0.55], p < 0.001), inadequate solute clearance (0.49 [0.26, 0.92], p = 0.026), and catheter-related noninfectious complications (0.41 [0.17, 0.97], p = 0.041) in the TM group compared with the non-TM group. CONCLUSION: This study indicated real-world associations between TM usage and reduction in patient survival and technique survival through a multicenter prospective cohort.

Structural insights into target DNA recognition by R2R3-MYB transcription factors.

As the largest group of MYB family transcription factors, R2R3-MYB proteins play essential roles during plant growth and development. However, the structural basis underlying how R2R3-MYBs recognize the target DNA remains elusive. Here, we report the crystal structure of Arabidopsis WEREWOLF (WER), an R2R3-MYB protein, in complex with its target DNA. Structural analysis showed that the third α-helices in both the R2 and R3 repeats of WER fit in the major groove of the DNA, specifically recognizing the DNA motif 5'-AACNGC-3'. In combination with mutagenesis, in vitro binding and in vivo luciferase assays, we showed that K55, N106, K109 and N110 are critical for the function of WER. Although L59 of WER is not involved in DNA binding in the structure, ITC analysis suggested that L59 plays an important role in sensing DNA methylation at the fifth position of cytosine (5mC). Like 5mC, methylation at the sixth position of adenine (6mA) in the AAC element also inhibits the interaction between WER and its target DNA. Our study not only unravels the molecular basis of how WER recognizes its target DNA, but also suggests that 5mC and 6mA modifications may block the interaction between R2R3-MYB transcription factors and their target genes.

Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice.

BACKGROUND: Congenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs. METHODS AND RESULTS: Patients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3 ) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae. CONCLUSION: Our findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

miR-185 affected the EMT, cell viability, and proliferation via DNMT1/MEG3 pathway in TGF-ß1-induced renal fibrosis.

Kidney fibrosis is usually the final manifestation of a wide variety of renal diseases. Recent years, research reported that long non-coding RNAs (lncRNAs) played important roles in a variety of human diseases. However, the role and underlying mechanisms of lncRNAs in kidney fibrosis were complicated and largely unclear. In our study, we constructed the cell model of renal fibrosis in HK2 cells using transforming growth factor ß1 (TGF-ß1) and found that lncRNA maternally expressed gene 3 (MEG3) was downregulated in TGF-ß1-induced renal fibrosis. We then found that overexpressed MEG3 inhibited the TGF-ß1-induced promotion of epithelial-mesenchymal transition, cell viability, and proliferation. Furthermore, we demonstrated that DNA methyltransferases 1 (DNMT1) regulated the MEG3 expression by altering the CpGs methylation level of MEG3 promoter in TGF-ß1-induced renal fibrosis. In addition, we further revealed that miR-185 could regulate the DNMT1 expression and thus, modulate the MEG3 in TGF-ß1-induced renal fibrosis. Ultimately, our study illustrated that the modulation of the miR-185/ DNMT1/ MEG3 pathway exerted important roles in TGF-ß1-induced renal fibrosis. In summary, our finding displayed a novel regulatory mechanism for TGF-ß1-induced renal fibrosis, which provided a new potential therapeutic target for renal fibrosis.

Boron doped carbon dots as a multifunctional fluorescent probe for sorbate and vitamin B12.

Boron doped carbon dots (B-CD) were synthesized by a one-step hydrothermal method using phenylboronic acid as the starting material. They have an average size of about 3.3 nm, with excitation/emission wavelength of 247/323 nm and a quantum yield of 12%. The B-CD is shown to be viable fluorescent probe for sorbate (PS) and vitamin B12 (VB12). The fluorescence (FL) of the B-CD is quenched in the presence of PS or VB12 mainly coming from inner filter effect (IFE), but Förster resonance energy transfer (FRET) from the B-CD (as a donor) to PS/VB12 (as an acceptor) cannot be excluded. The probe enables PS to be detected by fluorometry with a linear response in the 0.20-24 µM concentration range and a 6.1 nM detection limit (at 3σ/slope). For VB12, the data are 0.20-30 µM and 8.0 nM. Graphical abstract Boron doped carbon dots (B-CD) as a probe was prepared by phenylboronic acid as single starting material via one-step hydrothermal method, which has remarkable selectivity and high sensitivity for monitoring PS/VB12. The fluorescence quenching of B-CD by PS/VB12 mainly comes from inner filter effect.

Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis.

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin-proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers.

Modified nano zero-valent iron coupling microorganisms to degrade BDE-209: Degradation pathways and microbial responses.

Polybrominated diphenyl ethers (PBDEs) in soil and groundwater have garnered considerable attention owing to the significant bioaccumulation potential and toxicity. Currently, the coupling treatment method of nano zero-valent iron (nZVI) with dehalogenation microorganisms is a research hotspot in the field of PBDE degradation. In this study, various systems were established within anaerobic environments, including the nZVI-only system, microorganism-only system, and the nZVI + microorganisms system. The aim was to investigate the degradation pathway of BDE-209 and elucidate the degradation mechanism within the coupled system. The results indicated that the degradation efficiency of the coupled system was better than that of the nZVI-only or microorganism-only system. Two modified nZVI (carboxymethyl cellulose and polyacrylamide) were prepared to improve the coupling degradation efficiency. CMC-nZVI showed the highest stability, and the coupled system consisting of microorganisms and CMC-nZVI showed the best degradation effect among all of the systems in this study, reaching 89.53% within 30 days. Furthermore, 22 intermediate products were detected in the coupling systems. Notably, changing the inoculation time did not significantly improve the degradation effect. The expression changes of the two reductive dehalogenase genes, e.g. TceA and Vcr, reflected the stress response and self-recovery ability of the dehalogenating bacteria, indicating such genes can be used as biomarker for evaluating the degradation performance of the coupling system. These findings provide a better understanding about the mechanism of coupling debromination process and the direction for the optimization and on-site repair of coupled systems.

A Novel Ratio Probe Based on Mixing of Thiocyanuric Acid- Enhanced Silver Nanoclusters with N, S Co-Doped Carbon Quantum Dots for Detecting Sodium 2,3-Dimercapto Propanesulfonic Acid.

BACKGROUND: The ratio fluorescent probe (RF-probe) has the characteristics of self-calibration and eliminating the influence of experimental factors (such as probe concentration, excitation intensity stability, and solution environment) in quantitative assays based on the linear relationship between the intensity ratio of two emission peaks and the concentration of analyte, especially in a complex biological matrix. OBJECTIVE: High-luminescent Ag nanoclusters (AgNCs) were prepared at room temperature due to aggregation-induced emission (AIE) through the incorporation of trithiocyanuric acid (TA). Subsequently, a new RF-probe based on mixing of AgNCs-TA with nitrogen and sulfur co-doped carbon quantum dots (N, S-CQDs) was prepared for sensitively and selectively assaying sodium 2, 3-dimercaptopropane-1-sulfonate (DMPS). METHODS: The fluorescence of N, S-CQDs was quenched in the presence of the AgNCs-TA mainly deriving from the inner filter effect (IFE), and its fluorescence intensities at 440 and 650 nm could recover and drop upon the addition of DMPS (λex = 370 nm). RESULTS: The RF-probe enables DMPS to be detected by fluorometry with a linear response in the 0.67-30.0 µmol/L concentration range and a 54.7 nmol/L detection limit (at 3σ/slope). At the same time, we also used the labeled recovery method to confirm the reliability of the method. The recoveries were 97.93-106.33%, and the corresponding standard deviations (RSD) were less than 1.87%. CONCLUSION: The N, S-CQDs/AgNCs-TA RF-probe can also semi-quantitatively monitor DMPS by naked eyes. HIGHLIGHTS: The mechanism of fluorescence enhancement of the AgNCs by TA also were investigated by the N, S-CQDs/AgNCs-TA-DMPS system. What's more, the RF-probe of N, S-CQDs/AgNCs-TA was successfully utilized to monitor DMPS in real samples.

Radiomics-Based Method for Predicting the Glioma Subtype as Defined by Tumor Grade, IDH Mutation, and 1p/19q Codeletion.

Gliomas are among the most common types of central nervous system (CNS) tumors. A prompt diagnosis of the glioma subtype is crucial to estimate the prognosis and personalize the treatment strategy. The objective of this study was to develop a radiomics pipeline based on the clinical Magnetic Resonance Imaging (MRI) scans to noninvasively predict the glioma subtype, as defined based on the tumor grade, isocitrate dehydrogenase (IDH) mutation status, and 1p/19q codeletion status. A total of 212 patients from the public retrospective The Cancer Genome Atlas Low Grade Glioma (TCGA-LGG) and The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) datasets were used for the experiments and analyses. Different settings in the radiomics pipeline were investigated to improve the classification, including the Z-score normalization, the feature extraction strategy, the image filter applied to the MRI images, the introduction of clinical information, ComBat harmonization, the classifier chain strategy, etc. Based on numerous experiments, we finally reached an optimal pipeline for classifying the glioma tumors. We then tested this final radiomics pipeline on the hold-out test data with 51 randomly sampled random seeds for reliable and robust conclusions. The results showed that, after tuning the radiomics pipeline, the mean AUC improved from 0.8935 (±0.0351) to 0.9319 (±0.0386), from 0.8676 (±0.0421) to 0.9283 (±0.0333), and from 0.6473 (±0.1074) to 0.8196 (±0.0702) in the test data for predicting the tumor grade, IDH mutation, and 1p/19q codeletion status, respectively. The mean accuracy for predicting the five glioma subtypes also improved from 0.5772 (±0.0816) to 0.6716 (±0.0655). Finally, we analyzed the characteristics of the radiomic features that best distinguished the glioma grade, the IDH mutation, and the 1p/19q codeletion status, respectively. Apart from the promising prediction of the glioma subtype, this study also provides a better understanding of the radiomics model development and interpretability. The results in this paper are replicable with our python codes publicly available in github.

Regulation of gene expression by glycolytic and gluconeogenic enzymes.

Gene transcription and cell metabolism are two fundamental biological processes that mutually regulate each other. Upregulated or altered expression of glucose metabolic genes in glycolysis and gluconeogenesis is a major driving force of enhanced aerobic glycolysis in tumor cells. Importantly, glycolytic and gluconeogenic enzymes in tumor cells acquire moonlighting functions and directly regulate gene expression by modulating chromatin or transcriptional complexes. The mutual regulation between cellular metabolism and gene expression in a feedback mechanism constitutes a unique feature of tumor cells and provides specific molecular and functional targets for cancer treatment.

Feasibility of source-free DAS logging for next-generation borehole imaging.

Characterizing and monitoring geologic formations around a borehole are crucial for energy and environmental applications. However, conventional wireline sonic logging usually cannot be used in high-temperature environments nor is the tool feasible for long-term monitoring. We introduce and evaluate the feasibility of a source-free distributed-acoustic-sensing (DAS) logging method based on borehole DAS ambient noise. Our new logging method provides a next-generation borehole imaging tool. The tool is source free because it uses ever-present ambient noises as sources and does not need a borehole sonic source that cannot be easily re-inserted into a borehole after well completion for time-lapse monitoring. The receivers of our source-free DAS logging tool are fiber optic cables cemented behind casing, enabling logging in harsh, high-temperature environments, and eliminating the receiver repeatability issue of conventional wireline sonic logging for time-lapse monitoring. We analyze a borehole DAS ambient noise dataset to obtain root-mean-squares (RMS) amplitudes and use these amplitudes to infer subsurface elastic properties. We find that the ambient noise RMS amplitudes correlate well with anomalies in conventional logging data. The source-free DAS logging tool can advance our ability to characterize and monitor subsurface geologic formations in an efficient and cost-effective manner, particularly in high-temperature environments such as geothermal reservoirs. Further validation of the source-free DAS logging method using other borehole DAS ambient noise data would enable the new logging tool for wider applications.

Structural insights into partner selection for MYB and bHLH transcription factor complexes.

MYB and basic helix-loop-helix (bHLH) transcription factors form complexes to regulate diverse metabolic and developmental processes in plants. However, the molecular mechanisms responsible for MYB-bHLH interaction and partner selection remain unclear. Here, we report the crystal structures of three MYB-bHLH complexes (WER-EGL3, CPC-EGL3 and MYB29-MYC3), uncovering two MYB-bHLH interaction modes. WER and CPC are R2R3- and R3-type MYBs, respectively, but interact with EGL3 through their N-terminal R3 domain in a similar mode. A single amino acid of CPC, Met49, is crucial for competition with WER to interact with EGL3. MYB29, a R2R3-type MYB transcription factor, interacts with MYC3 by its C-terminal MYC-interaction motif. The WER-EGL3 and MYB29-MYC3 binding modes are widely applied among MYB-bHLH complexes in Arabidopsis and evolve independently in plants.

Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4.

METTL4 belongs to a subclade of MT-A70 family members of methyltransferase (MTase) proteins shown to mediate N6-adenosine methylation for both RNA and DNA in diverse eukaryotes. Here, we report that Arabidopsis METTL4 functions as U2 snRNA MTase for N6-2'-O-dimethyladenosine (m6Am) in vivo that regulates flowering time, and specifically catalyzes N6-methylation of 2'-O-methyladenosine (Am) within a single-stranded RNA in vitro. The apo structures of full-length Arabidopsis METTL4 bound to S-adenosyl-L-methionine (SAM) and the complex structure with an Am-containing RNA substrate, combined with mutagenesis and in vitro enzymatic assays, uncover a preformed L-shaped, positively-charged cavity surrounded by four loops for substrate binding and a catalytic center composed of conserved residues for specific Am nucleotide recognition and N6-methylation activity. Structural comparison of METTL4 with the mRNA m6A enzyme METTL3/METTL14 heterodimer and modeling analysis suggest a catalytic mechanism for N6-adenosine methylation by METTL4, which may be shared among MT-A70 family members.

The Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study: Design and methods.

OBJECTIVES: The primary objective of the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study is to explore potential predictors and their effects on patient survival, technique survival, and the occurrence of infectious and noninfectious complications. DESIGN: The PDTAP study is a national-level cohort study in China. A newly developed PD telemedicine application provided a unique and convenient way to collect multicenter, structured data across units. SETTING: The PDTAP study was underway in 27 hospitals from 14 provinces located at 7 geographical regions (northwest, northeast, north, central, southwest, southeast, and south) in China. PARTICIPANTS: Our study aims to enroll at least 7000 adult patients with end-stage renal disease receiving PD. METHODS: Approval has been obtained through the ethics committees of all hospitals. All participants signed the informed consent form after the center had received ethics board approval in accordance with the Declaration of Helsinki. MAIN OUTCOME MEASURES: Patient survival, technique survival, hospitalization, and the occurrence of infectious and noninfectious complications. CONCLUSIONS: The PDTAP study aims to explore potential predictors and their effects on patient survival, technique survival, and infectious and noninfectious complications using a newly developed PD telemedicine system to collect multicenter, structured data in real-world practice. Substantial and transformable findings in relation to PD practices were expected. This study also developed a national-level infrastructure for further collaboration and ancillary investigation.

Impact of Preprocessing and Harmonization Methods on the Removal of Scanner Effects in Brain MRI Radiomic Features.

In brain MRI radiomics studies, the non-biological variations introduced by different image acquisition settings, namely scanner effects, affect the reliability and reproducibility of the radiomics results. This paper assesses how the preprocessing methods (including N4 bias field correction and image resampling) and the harmonization methods (either the six intensity normalization methods working on brain MRI images or the ComBat method working on radiomic features) help to remove the scanner effects and improve the radiomic feature reproducibility in brain MRI radiomics. The analyses were based on in vitro datasets (homogeneous and heterogeneous phantom data) and in vivo datasets (brain MRI images collected from healthy volunteers and clinical patients with brain tumors). The results show that the ComBat method is essential and vital to remove scanner effects in brain MRI radiomic studies. Moreover, the intensity normalization methods, while not able to remove scanner effects at the radiomic feature level, still yield more comparable MRI images and improve the robustness of the harmonized features to the choice among ComBat implementations.

A pH-triggered fluorescence-switchable extracellular vesicle for tracing drug release and improving drug delivery.

Extracellular vesicles have shown great potential in drug delivery for clinical applications. However, some obstacles still need to be overcome before their clinical translation, including on demand release of drugs to improve the efficacy and monitoring of the drug release process to ascertain drug dosage. Herein, a pH-triggered fluorescence-switchable extracellular vesicle as a smart nanocarrier is fabricated by loading zwitterionic fluorescent carbon dots (CDs) into macrophage cell-secreted vesicles to achieve improved drug delivery and real-time monitoring of drug release. When circulating in the blood, the zwitterionic CDs loaded in the vesicles can tightly bind the chemotherapeutic drug DOX through electrostatic interactions to avoid premature drug unload. The nanocarriers have a long blood circulation half-life of 15.12 h and a high tumor accumulation of 9.88% ID/g. Meanwhile, the fluorescence of the CDs is in the "off" state due to the fluorescence inner filter effect (IFE) between the DOX and the CDs. When the nanocarriers enter the tumor cells, the low pH of the lysosome leads to charge reversal of the CDs. DOX can be quickly released through electrostatic repulsion and the fluorescence of the CDs turns "on" after the release of the drugs, thus enabling an improved drug delivery and real-time tracking of the drug release process.