Preparation of CNT/CNF/PDMS/TPU Nanofiber-Based Conductive Films Based on Centrifugal Spinning Method for Strain Sensors.

Flexible conductive films are a key component of strain sensors, and their performance directly affects the overall quality of the sensor. However, existing flexible conductive films struggle to maintain high conductivity while simultaneously ensuring excellent flexibility, hydrophobicity, and corrosion resistance, thereby limiting their use in harsh environments. In this paper, a novel method is proposed to fabricate flexible conductive films via centrifugal spinning to generate thermoplastic polyurethane (TPU) nanofiber substrates by employing carbon nanotubes (CNTs) and carbon nanofibers (CNFs) as conductive fillers. These fillers are anchored to the nanofibers through ultrasonic dispersion and impregnation techniques and subsequently modified with polydimethylsiloxane (PDMS). This study focuses on the effect of different ratios of CNTs to CNFs on the film properties. Research demonstrated that at a 1:1 ratio of CNTs to CNFs, with TPU at a 20% concentration and PDMS solution at 2 wt%, the conductive films crafted from these blended fillers exhibited outstanding performance, characterized by electrical conductivity (31.4 S/m), elongation at break (217.5%), and tensile cycling stability (800 cycles at 20% strain). Furthermore, the nanofiber-based conductive films were tested by attaching them to various human body parts. The tests demonstrated that these films effectively respond to motion changes at the wrist, elbow joints, and chest cavity, underscoring their potential as core components in strain sensors.

Pyrazine-based iron metal organic frameworks (Fe-MOFs) with modulated O-Fe-N coordination for enhanced hydroxyl radical generation in Fenton-like process.

Rational design of coordination environment of Fe-based metal-organic frameworks (Fe-MOFs) is still a challenge in achieving enhanced catalytic activity for Fenten-like advanced oxidation process. Here in, novel porous Fe-MOFs with modulated O-Fe-N coordination was developed by configurating amino terephthalic acid (H2ATA) and pyrazine-dicarboxylic acid (PzDC) (Fe-ATA/PzDC-7:3). PzDC ligands introduce pyridine-N sites to form O-Fe-N coordination with lower binding energy, which affect the local electronic environment of Fe-clusters in Fe-ATA, thus decreased its interfacial H2O2 activation barrier. O-Fe-N coordination also accelerate Fe(II)/Fe(III) cycling of Fe-clusters by triggering the reactive oxidant species mediated Fe(III) reduction. As such, Fe-ATA/PzDC-7:3/H2O2 system exhibited excellent degradation performance for typical antibiotic sulfamethoxazole (SMX), in which the steady-state concentration of hydroxyl radical (OH) was 1.6 times higher than that of unregulated Fe-ATA. Overall, this study highlights the role of O-Fe-N coordination and the electronic environment of Fe-clusters on regulating Fenton-like catalytic performance, and provides a platform for precise engineering of Fe-MOFs.

Optically Active Oxygen Defects in Titanium Dioxide Doped with Inorganic Acid Ions.

Doping inorganic acid ions represents a promising pathway to improving the photocatalytic activity of TiO2, and oxygen vacancy has been regarded as the determinant factor for photocatalytic activity. A series of samples doped with Cl-, NO3-, and SO42- was prepared via a simple sol-gel method. Two different oxygen vacancies in the crystal layer of NO3-/TiO2 and Cl-/TiO2 were found, and those are [Ti3+]-V0-[Ti3+] and [Ti3+]-Cl, respectively. The photocurrent of NO3-/TiO2 with [Ti3+]-V0-[Ti3+] is significantly greater than that of Cl-/TiO2 with [Ti3+]-Cl. The least oxygen vacancy is in the gel layer of SO42-/TiO2, and the negligible photocurrent is due to difficulty in forming a stable sol. Furthermore, the process conditions for the application of TiO2 were investigated in this work. The optimal process parameters are to adjust the solution to pH = 3 during sol-gel preparation, to adopt 550 °C as the calcination temperature, and to use an alkaline electrolyte, while the rest of the preparation conditions remain unchanged. This work reveals a new avenue for designing efficient photocatalysts for air pollutant degradation.

Epicatechin-Promoted Formation of Acrylamide from 3-Aminopropionamide Via Postoxidative Reaction of B-Ring.

The role of thermally generated 3-aminopropionamide as an intermediate in acrylamide formation in the Maillard reaction has been well established. Herein, the effect of epicatechin on the conversion of 3-aminopropionamide into acrylamide under oxidative conditions was investigated at 160-220 °C. Epicatechin promoted acrylamide generation and 3-aminopropionamide degradation. The stable isotope-labeling technique combined with UHPLC-Orbitrap-MS/MS analysis showed adduct formation between 3-aminopropionamide and the oxidized B ring of epicatechin to form a Schiff base. This initially formed Schiff base could directly degrade to acrylamide, undergo reduction or dehydration to other intermediates, and subsequently generate acrylamide. Based on accurate mass analysis, five intermediates with intact or dehydrated C rings were tentatively identified. Furthermore, reaction pathways were proposed that were supported by the changes in the levels of adducts formed during heating. To the authors' knowledge, this study is the first to reveal pathways through which flavanols promoted the formation of acrylamide in Maillard reactions.

Single-crystalline hole-transporting layers for efficient and stable organic light-emitting devices.

Efficient charge-carrier injection and transport in organic light-emitting devices (OLEDs) are essential to simultaneously achieving their high efficiency and long-term stability. However, the charge-transporting layers (CTLs) deposited by various vapor or solution processes are usually in amorphous forms, and their low charge-carrier mobilities, defect-induced high trap densities and inhomogeneous thickness with rough surface morphologies have been obstacles towards high-performance devices. Here, organic single-crystalline (SC) films were employed as the hole-transporting layers (HTLs) instead of the conventional amorphous films to fabricate highly efficient and stable OLEDs. The high-mobility and ultrasmooth morphology of the SC-HTLs facilitate superior interfacial characteristics of both HTL/electrode and HTL/emissive layer interfaces, resulting in a high Haacke's figure of merit (FoM) of the ultrathin top electrode and low series-resistance joule-heat loss ratio of the SC-OLEDs. Moreover, the thick and compact SC-HTL can function as a barrier layer against moisture and oxygen permeation. As a result, the SC-OLEDs show much improved efficiency and stability compared to the OLEDs based on amorphous or polycrystalline HTLs, suggesting a new strategy to developing advanced OLEDs with high efficiency and high stability.

Mini-MEndR: a miniaturized 96-well predictive assay to evaluate muscle stem cell-mediated repair.

Background: Functional evaluation of molecules that are predicted to promote stem cell mediated endogenous repair often requires in vivo transplant studies that are low throughput and hinder the rate of discovery. To offer greater throughput for functional validation studies, we miniaturized, simplified and expanded the functionality of a previously developed muscle endogenous repair (MEndR) in vitro assay that was shown to capture significant events of in vivo muscle endogenous repair. Methods: The mini-MEndR assay consists of miniaturized cellulose scaffolds designed to fit in 96-well plates, the pores of which are infiltrated with human myoblasts encapsulated in a fibrin-based hydrogel to form engineered skeletal muscle tissues. Pre-adsorbing thrombin to the cellulose scaffolds facilitates in situ tissue polymerization, a critical modification that enables new users to rapidly acquire assay expertise. Following the generation of the 3D myotube template, muscle stem cells (MuSCs), enriched from digested mouse skeletal muscle tissue using an improved magnetic-activated cell sorting protocol, are engrafted within the engineered template. Murine MuSCs are fluorescently labeled, enabling co-evaluation of human and mouse Pax7+ cell responses to drug treatments. A regenerative milieu is introduced by injuring the muscle tissue with a myotoxin to initiate endogenous repair "in a dish". Phenotypic data is collected at endpoints with a high-content imaging system and is analyzed using ImageJ-based image analysis pipelines. Results: The miniaturized format and modified manufacturing protocol cuts reagent costs in half and hands-on seeding time ~ threefold, while the image analysis pipelines save 40 h of labour. By evaluating multiple commercially available human primary myoblast lines in 2D and 3D culture, we establish quality assurance metrics for cell line selection that standardizes myotube template quality. In vivo outcomes (enhanced muscle production and Pax7+ cell expansion) to a known modulator of MuSC mediated repair (p38/ß MAPK inhibition) are recapitulated in the miniaturized culture assay, but only in the presence of stem cells and the regenerative milieu. Discussion: The miniaturized predictive assay offers a simple, scaled platform to co-investigate human and mouse skeletal muscle endogenous repair molecular modulators, and thus is a promising strategy to accelerate the muscle endogenous repair discovery pipeline. Supplementary Information: The online version contains supplementary material available at 10.1186/s44330-024-00005-4.

Altered gut microbe metabolites in patients with alcohol­induced osteonecrosis of the femoral head: An integrated omics analysis.

Excessive alcohol consumption is considered to be a major risk factor of alcohol-induced osteonecrosis of the femoral head (AONFH). The gut microbiota (GM) has been reported to aid in the regulation of human physiology and its composition can be altered by alcohol consumption. The aim of the present study was to improve the understanding of the GM and its metabolites in patients with AONFH. Metabolomic sequencing and 16S rDNA analysis of fecal samples were performed using liquid chromatography-mass spectrometry to characterize the GM of patients with AONFH and healthy normal controls (NCs). Metagenomic sequencing of fecal samples was performed to identify whether GM changes on the species level were associated with the expression of gut bacteria genes or their associated functions in patients with AONFH. The abundance of 58 genera was found to differ between the NC group and the AONFH group. Specifically, Klebsiella, Holdemanella, Citrobacter and Lentilactobacillus were significantly more abundant in the AONFH group compared with those in the NC group. Metagenomic sequencing demonstrated that the majority of the bacterial species that exhibited significantly different abundance in patients with AONFH belonged to the genus Pseudomonas. Fecal metabolomic analysis demonstrated that several metabolites were present at significantly different concentrations in the AONFH group compared with those in the NC group. These metabolites were products of vitamin B6 metabolism, retinol metabolism, pentose and glucuronate interconversions and glycerophospholipid metabolism. In addition, these changes in metabolite levels were observed to be associated with the altered abundance of specific bacterial species, such as Basidiobolus, Mortierella, Phanerochaete and Ceratobasidium. According to the results of the present study, a comprehensive landscape of the GM and metabolites in patients with AONFH was revealed, suggesting the existence of interplay between the gut microbiome and metabolome in AONFH pathogenesis.

Efficient Near-Infrared Fluorophores Based on Cyanostyrene Derivatives for Two-Photon Fluorescence Bioimaging.

Organic fluorescent materials with red/near-infrared (NIR) emission are highly promising for use in biotechnology due to their exceptional advantages. However, traditional red/NIR fluorophores often exhibit weak emission at high concentrations or in an aggregated state due to the aggregate-caused quenching effect, which severely limits their applicability in biological imaging. To address this challenge, we developed a series of cyanostyrene derivatives with aggregation-induced emission characteristics, including 2,3-Bis-(4-styryl-phenyl)-but-2-enedinitrile (DPB), 2,3-Bis-{4-[2-(4-methoxy- phenyl)-vinyl]-phenyl}-but-2-enedinitrile (DOB), 2,3-Bis-{4-[2-(4-diphenylamino- phenyl)-vinyl]-phenyl}-but-2-enedinitrile (DTB), and 2,3-Bis-[4-(2-{4-[phenyl- (4-triphenylvinyl-phenyl)-amino]-phenyl}-vinyl)- phenyl]-but-2-enedinitrile (DTTB). Notably, these compounds exhibited intense solid state fluorescence owing to AIE effect, especially DTTB shows NIR emission with high solid state quantum efficiency (712 nm, ΦF=14.2%). Then we prepared DTTB@PS-PEG NPs nanoparticles by encapsulating DTTB with the amphiphilic polymer polystyrene-polyethylene glycol (PS-PEG). Importantly, DTTB@PS-PEG NPs exhibited highly efficient NIR luminescence (ΦF=28.7%) and a large two-photon absorption cross-section (1900 GM) under 800 nm laser excitation. The bright two-photon fluorescence of DTTB@PS-PEG indicated that it can be a highly promising candidate for two-photon fluorescence probe. Therefore, this work provides valuable insights for the design of highly efficient and NIR-emitting two-photon fluorescent probes.

16th GCC Closed Forum: ICH M10 implementation; NGS, qPCR/dPCR, flow cytometry validation; tissue biomarkers; IS response; immunogenicity harmonization; bioanalytical industry status.

The 16th GCC Closed Forum was held in Orlando, FL, USA, on 23 June 2023. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: IS response, flow cytometry, changes to the bioanalytical industry, NGS assays, biomarker assay for tissues, dPCR validation, immunogenicity harmonization and ICH M10 implementation. Conclusions and consensus from discussions of these topics are included in this article.

Circ_0007386 Promotes the Progression of Hepatocellular Carcinoma Through the miR-507/ CCNT2 Axis.

Background: Circular RNAs (circRNAs) have been shown to play a crucial role in the initiation and development of Hepatocellular carcinoma (HCC). However, the mechanism and function of circ_0007386 in HCC are still unknown. Methods: Circ_0007386 expression level in HCC tissues, and HCC cell lines was further analyzed by qRT-PCR. Agarose gel electrophoresis and Sanger sequencing were used to figure out the structure of circ_0007386. The involvement of circ_0007386 in HCC development was evaluated by experimental investigations conducted in both laboratory settings (in vitro) and living organisms (in vivo). RNA immunoprecipitation, Western blotting, luciferase reporter assay and fluorescence in situ hybridization (FISH) were applied for finding out the interaction among circ_0007386, miR-507 and CCNT2. To assess the connection between circ_0007386 and lenvatinib resistance, lenvatinib-resistant HCC cell lines were employed. Results: The expression of circ_0007386 was found to increase in HCC tissues, and it was observed to be associated with a worse prognosis. Overexpression of circ_0007386 stimulated HCC cells proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) while silencing of circ_0007386 resulted in the opposite effect. Mechanistic investigations revealed that circ_0007386 acted as a competing endogenous RNA of miR-507 to prevent CCNT2 downregulation. Downregulating miR-507 or overexpressing CCNT2 could reverse phenotypic alterations that originated from inhibiting of circ_0007386. Importantly, circ_0007386 determines the resistance of hepatoma cells to lenvatinib treatment. Conclusion: Circ_0007386 advanced HCC progression and lenvatinib resistance through the miR-507/ CCNT2 axis. Meanwhile, circ_0007386 served as a potential biomarker and therapeutic target in HCC patients.

Distinct signatures of gut microbiota and metabolites in primary biliary cholangitis with poor biochemical response after ursodeoxycholic acid treatment.

BACKGROUND: About 1/3 of primary biliary cholangitis (PBC) patients suffered from poor response worldwide. And these patients present intestinal disturbances. We aimed to identify signatures of microbiota and metabolites in PBC patients with poor response, comparing to patients with response. METHODS: This study enrolled 25 subjects (14 PBC patients with response and 11 PBC patients with poor response). Metatranscriptomics and metabolomics analysis were carried out on their fecal. RESULTS: PBC patients with poor response had significant differences in the composition of bacteria, characterized by decreased Gemmiger etc. and increased Ruminococcus etc. The differential microbiota functions characterized by decreased abundance of elongation factor Tu and elongation factor G base on the KO database, as well as decreased abundance of Replicase large subunit etc. based on the SWISS-PROT database. PBC with poor response also had significant differences in 17 kinds of bacterial metabolites, characterized by decreased level of metabolites vital in bile acids metabolism pathway (L-Cysteine etc.) and the all-trans-Retinoic acid, a kind of immune related metabolite. The altered microbiota was associated with the differential expressed metabolites and clinical liver function indicators. 1 bacterial genera, 2 bacterial species and 9 metabolites simultaneously discriminated PBC with poor response from PBC with response with high accuracy. CONCLUSION: PBC patients with poor response exhibit unique changes in microbiota and metabolite. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential prediction of PBC with poor prognosis.

Is systemic inflammation a missing link between cardiometabolic index with mortality? Evidence from a large population-based study.

BACKGROUND: This study sought to elucidate the associations of cardiometabolic index (CMI), as a metabolism-related index, with all-cause and cardiovascular mortality among the older population. Utilizing data from the National Health and Nutrition Examination Survey (NHANES), we further explored the potential mediating effect of inflammation within these associations. METHODS: A cohort of 3029 participants aged over 65 years old, spanning six NHANES cycles from 2005 to 2016, was enrolled and assessed. The primary endpoints of the study included all-cause mortality and cardiovascular mortality utilizing data from National Center for Health Statistics (NCHS). Cox regression model and subgroup analysis were conducted to assess the associations of CMI with all-cause and cardiovascular mortality. The mediating effect of inflammation-related indicators including leukocyte, neutrophil, lymphocyte, systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR) were evaluated to investigate the potential mechanism of the associations between CMI and mortality through mediation package in R 4.2.2. RESULTS: The mean CMI among the enrolled participants was 0.74±0.66, with an average age of 73.28±5.50 years. After an average follow-up period of 89.20 months, there were 1,015 instances of all-cause deaths and 348 cardiovascular deaths documented. In the multivariable-adjusted model, CMI was positively related to all-cause mortality (Hazard Ratio (HR)=1.11, 95% CI=1.01-1.21). Mediation analysis indicated that leukocytes and neutrophils mediated 6.6% and 13.9% of the association of CMI with all-cause mortality. CONCLUSION: Elevated CMI is positively associated with all-cause mortality in the older adults. The association appeared to be partially mediated through inflammatory pathways, indicating that CMI may serve as a valuable indicator for poor prognosis among the older population.

Inhibition of the STAT3-EPHX2 axis promotes regression of ulcerative colitis by treatment with novel porphyrin derivative.

LD4, a novel porphyrin derivative, has attracted much attention for its excellent anti-inflammatory properties. It can promote the healing of colonic mucosa, reduce inflammatory response, regulate oxidative stress, and thus improve ulcerative colitis (UC) symptoms. However, the specific signaling pathways of LD4-PDT involved in UC have not been explored. The present study aimed to elucidate the effects of LD4 on UC and to investigate the underlying mechanisms both in vivo and in vitro. We classified and screened the LD4-PDT proteomic data to obtain key targets. Proteomic data revealed that EPHX2 and STAT3 are key targets of LD4-PDT for UC. Moreover, transcription factor STAT3 positively regulates the expression of EPHX2. Inhibiting EPHX2 can prevent the activation of NF-κB signaling pathway. Next, through pharmacological inhibition experiments, we confirmed that LD4-PDT can reduce intestinal inflammation by inhibiting STAT3-EPHX2 axis. However, by treating normal intestinal epithelial cells and colon cancer cells with TPPU and Stattic, our data confirmed that the STAT3-EPHX2 axis does not exist in colon cancer. In this study, we demonstrated that the transcription factor STAT3 can positively regulate the expression of EPHX2 in normal colon. LD4 can alleviate UC by inhibiting the STAT3-EPHX2 axis, but this axis does not exist in colon cancer. LD4-PDT may become a new and effective method for treating UC.

NOTCH3 as a prognostic biomarker and its correlation with immune infiltration in gastrointestinal cancers.

NOTCH receptor 3 (NOTCH3) is known to regulate the transcription of oncogenes or tumor suppressor genes, thereby playing a crucial role in tumor development, invasion, maintenance, and chemotherapy resistance. However, the specific mechanism of how NOTCH3 drives immune infiltration in gastrointestinal cancer remains uncertain. The expression of NOTCH3 was analyzed through Western blot, PCR, Oncomine database, and the Tumor Immune Estimation Resource (TIMER) site. Kaplan-Meier plotter, PrognoScan database, and gene expression profile interactive analysis (GEPIA) were used to assess the impact of NOTCH3 on clinical prognosis. The correlation between NOTCH3 expression and immune infiltration gene markers was investigated using TIMER and GEPIA. NOTCH3 was found to be commonly overexpressed in various types of gastrointestinal tumors and was significantly associated with poor prognosis. Furthermore, the expression level of NOTCH3 showed a significant correlation with the tumor purity of gastrointestinal tumors and the extent of immune infiltration by different immune cells. Our findings suggest that NOTCH3 may act as a crucial regulator of tumor immune cell infiltration and can serve as a valuable prognostic biomarker in gastrointestinal cancers.

[A nomogram for predicting residual back pain after percutaneous vertebroplasty for osteoporotic vertebral compression fractures].

OBJECTIVE: To construct percutaneous vertebroplasty for predicting osteoporotic vertebral compression fractures (OVCFs) nomogram of residual back pain (RBP) after percutaneous vertebroplasty(PVP). METHODS: Clinical data of 245 OVCFs patients who were performed PVP from January 2020 to December 2022 were retrospectively analyzed, including 47 males and 198 females, aged from 65 to 77 years old with an average of (71.47±9.03) years old, and were divided into RBP group and non-RBP group according to whether RBP occurred. Gender, age, comorbidities, fracture stage, body mass index (BMI), bone mineral density (BMD), visual analogue scale (VAS), Oswestry disability index (ODI) and other general information were collected; anterior vertebral height (AVH), anterior vertebral height ratio (AVH), anterior vertebral height ratio(AVHR), Cobb angle, intravertebral vacuum cleft (IVC), thoracolumbar fascia (TLF) injury, paravertebral muscle steatosis, injection volume and leakage of bone cement, bone cement dispersion pattern, anterior vertebral height recovery ratio (AVHRR), Cobb angle changes, etc. imaging parameters before operation and 24 h after operation were collected. Univariate analysis was performed to analysis above factors, and multivariate Logistic regression model was used to investigate independent risk factors for postoperative RBP, and Nomogram model was constructed and verified;receiver operating characteristic(ROC) curve and calibration curve were used to determine predictive performance and accuracy of the model, and Hosmer-Lemeshow (H-L) test was used for evaluation. The area under curve (AUC) of ROC was calculated, and Harrell consistency index (C index) was used to evaluate the predictive efficiency of model;decision curve analysis (DCA) was used to evaluate clinical practicability of model. RESULTS: There were 34 patients in RBP group and 211 patients in non-RBP group. There were no significant differences in gender, age, comorbidities, fracture stage, BMI, BMD, VAS, ODI, AVH, AVHR and Cobb angle between two groups (P>0.05). Univariate analysis showed 6 patients occurred IVC in RBP group and 13 patients in non-RBP, the number of IVC in RBP group was higher than that in non-RBP group (χ2=5.400, P=0.020);6 patients occuured TLF injury in RBP group and 11 patients in non-RBP group, the number of TLF injury in RBP group was higher than that in non-RBP group (χ2=7.011, P=0.008);In RBP group, 18 patients with grade 3 to 4 paraptebral steatosis and 41 patients in non-RBP group, RBP group was higher than non-RBP group (χ2=21.618, P<0.001), and the proportion of bone cement mass in RBP group was higher than non-RBP group (χ2=6.836, P=0.009). Multivariate Logistic regression analysis showed IVC (χ2=4.974, P=0.025), TLF injury (χ2=5.231, P=0.023), Goutallier grade of paravertebral steatosis >2 (χ2=15.124, P<0.001) and proportion of bone cement (χ2=4.168, P=0.038) were independent risk factors for RBP after PVP. ROC curve of model showed AUC of original model was 0.816[OR=2.862, 95%CI (0.776, 0.894), P<0.001]. The internal verification of model through 200 bootstrap samples showed the value of C index was 0.936, and calibration curve showed predicted probability curve was close to actual probability curve. H-L goodness of fit test results were χ2=5.796, P=0.670. DCA analysis results showed the decision curve was above None line and All line when the threshold value ranged from 6% to 71%. CONCLUSION: IVC, TLF combined injury, paravertebral muscle steatosis with Goutallier grade> 2, and bone cement diffusion with mass type are independent risk factors for RBP after PVP. The risk prediction model for RBP after PVP established has good predictive performance and good clinical practicability.

Regular Tetrahedron Model for the Assessment of High-Resolution Mass Spectrometry Data of Four-Way Fractionated Dissolved Organic Matter.

A regular tetrahedron model was established to pierce the fractionation of dissolved organic matter (DOM) among quaternary components by using high-resolution mass spectrometry. The model can stereoscopically visualize molecular formulas of DOM to show the preference to each component according to the position in a regular tetrahedron. A classification method was subsequently developed to divide molecular formulas into 15 categories related to fractionation ratios, the relative change of which was demonstrated to be convergent with the uncertainty of mass peak area. The practicality of the regular tetrahedron model was verified by seven kinds of sludge from waste leachate treatment and sewage wastewater treatment plants by using stratification of extracellular polymeric substances coupled with Orbitrap MS as an example, presenting the DOM chemodiversity in stratified sludge flocs. Sensitivity analysis proved that classification results were relatively stable with the perturbation of four model parameters. Multinomial logistic regression analysis could further help identify the effect of molecular properties on the fractionation of DOM based on the classification results of the regular tetrahedron model. This model offers a methodology for the assessment of specificity of sequential extraction on DOM from solid or semisolid components and simplifies the complex mathematical expression of fractionation coefficients for quaternary components.

NAMPT-targeting PROTAC and nicotinic acid co-administration elicit safe and robust anti-tumor efficacy in NAPRT-deficient pan-cancers.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved in vivo exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs.

Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

lncTIMP3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells via miR-214/Smad4 axis to relieve postmenopausal osteoporosis.

BACKGROUND: Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. METHODS: The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. RESULTS: The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. CONCLUSION: lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.