Two-Dimensional Liquid Chromatography Purified GC/C/IRMS Doping Control Method: Analysis of Endogenous and Exogenous Sources in Urine Samples from Asian Subjects Administered a Low Dose of AICAR.

AICAR (5-amino-4-imidazolecarboxyamide ribonucleoside), as a metabolic modulator, is classified in the S4 category by the World Anti-Doping Agency (WADA). Carbon Isotope Ratio Mass Spectrometry (CIR) is the mainstream method for distinguishing the endogenous and exogenous sources of AICAR in urine due to the significant individual difference in the concentration. The purpose of this study is to establish a gas chromatography combustion Isotope Ratio Mass Spectrometry (GC/C/IRMS) method for AICAR based on efficient two-dimensional liquid chromatography (2D-HPLC) separation. METHOD: In this study, an automated 2D-HPLC separation technique was used to separate and purify AICAR and endogenous reference substances in urine samples. Then, AICAR was derivatized with 3-TMS as the main derivative product, while the endogenous reference compounds remained in their original form. Subsequently, the developed GC/C/IRMS method was utilized for the detection of the target and reference substances. Followed, we evaluated the applicability of this method using urine samples from two Asian males administered a low dose of AICAR (3 grams). RESULTS: The advantages of this study include: 1) reduced sample pretreatment time: the established 2D-HPLC separation method can separate the target and endogenous reference substances in one step; 2) low interference: the isotope chromatograms have low background interference, and the separation of endogenous reference substances is purer; 3) more accurate result calculations: this method only requires derivatization and result correction for AICAR, with the endogenous reference substances measured in their original form, reducing biases from corrections of multiple substances. The detection method performed well, with a concentriton limit of 2500 ng/mL, meeting the needs of routine detection concentrations. The CIR results from volunteer samples indicated that samples collected within 16 hours post-administration exceeded the threshold set in the literature. CONCLUSION: This study successfully established a 2D-HPLC-GC/IRMS method that integrates CIR as the most stable indicator for distinguishing the internal and external sources of AICAR. After administering a low dose of AICAR to the Asian population, exogenous drug characteristics were manifested within 16 hours. This observation, when compared to the 40-hour detection window cited in the literature, suggests that the length of the detection window is positively correlated with the dosage of the test drug.

Microplastic exposure inhibits nitrate uptake and assimilation in wheat plants.

Microplastic (MP) contamination in soil severely impairs plant growth. However, mechanisms underlying the effects of MPs on plant nutrient uptake remain largely unknown. In this study, we revealed that NO3- content was significantly decreased in shoots and roots of wheat plants exposed to high concentrations (50-100 mg L-1) of MPs (1 µm and 0.1 µm; type: polystyrene) in the hydroponic solution. Isotope labeling experiments demonstrated that MP exposure led to a significant inhibition of NO3- uptake in wheat roots. Further analysis indicated that the presence of MPs markedly inhibited root growth and caused oxidative damage to the roots. Additionally, superoxide dismutase and peroxidase activities in wheat roots decreased under all MP treatments, whereas catalase and ascorbate peroxidase activities significantly increased under the 100 mg L-1 MP treatment. The transcription levels of most nitrate transporters (NRTs) in roots were significantly downregulated by MP exposure. Furthermore, exposure to MPs distinctly suppressed the activity of nitrate reductase (NR) and nitrite reductase (NiR), as well as the expression levels of their coding genes in wheat shoots. These findings indicate that a decline in root uptake area and root vitality, as well as in the expression of NRTs, NR, and NiR genes caused by MP exposure may have adverse effects on NO3- uptake and assimilation, consequently impairing normal growth of plants.

A nomogram based on neuron-specific enolase and substantia nigra hyperechogenicity for identifying cognitive impairment in Parkinson's disease.

Background: One in four individuals with Parkinson's disease (PD) experience cognitive impairment (CI). However, few practical models integrating clinical and neuroimaging biomarkers have been developed to address CI in PD. This study aimed to evaluate the correlation between circulating neuron-specific enolase (NSE) levels, substantia nigra hyperechogenicity (SNH), and cognitive function in PD and to develop a nomogram based on clinical and neuroimaging biomarkers for predicting CI in patients with PD. Methods: A total of 385 patients with PD who underwent transcranial sonography (TCS) from January 2021 to December 2022 at Beijing Tiantan Hospital, Capital Medical University, were recruited as the training cohort. For validation, 165 patients with PD treated from January 2023 to December 2023 were enrolled. Data for SNH, plasma NSE, and other clinical measures were collected, and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Logistic regression analysis was employed to select potential risk factors and establish a nomogram. The receiver operating characteristic curve and calibration curve were generated to evaluate the performance of the nomogram. Results: Patients with PD exhibiting CI displayed advanced age, elevated Unified PD Rating Scale-III (UPDRS-III) score, an increased percentage of SNH, higher levels of plasma NSE and homocysteine (Hcy), a larger SNH area, and lower education levels compared to PD patients without CI. Gender [odds ratio (OR) =0.561, 95% confidence interval (CI): 0.330-0.954, P=0.03], age (OR =1.039; 95% CI: 1.011-1.066; P=0.005), education level (OR =0.892; 95% CI: 0.842-0.954; P<0.001), UPDRS-III scores (OR =1.026; 95% CI: 1.009-1.043; P=0.003), plasma NSE concentration (OR =1.562; 95% CI: 1.374-1.776; P<0.001), and SNH (OR =0.545; 95% CI: 0.330-0.902; P=0.02) were independent predictors of CI in patients with PD. A nomogram developed using these six factors yielded a moderate discrimination performance with an area under the curve (AUC) of 0.823 (95% CI 0.781-0.864; P<0.001). The calibration curve demonstrated acceptable agreement between predicted outcomes and actual values. Validation further confirmed the reliability of the nomogram, with an AUC of 0.864 (95% CI: 0.805-0.922; P<0.001). Conclusions: The level of NSE in plasma and the SNH assessed by TCS are associated with CI in patients with PD. The proposed nomogram has the potential to facilitate the detection of cognitive decline in individuals with PD.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial.

OBJECTIVE: To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. METHODS: In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1. RESULTS: 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%). CONCLUSIONS: The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety. TRIAL REGISTRATION NUMBER: NCT05180851.

Screening anabolic androgenic steroids in human urine: an application of the state-of-the-art gas chromatography-Orbitrap high-resolution mass spectrometry.

Over the past few decades, anabolic androgenic steroids (AASs) have been abused in and out of competition for their performance-enhancing and muscle-building properties. Traditionally, AASs were commonly detected using gas chromatography-mass spectrometry in the initial testing procedure for doping control purposes. Gas chromatography-Orbitrap high-resolution mass spectrometry (GC-Orbitrap-HRMS) is a new technology that has many advantages in comparison with GC-MS (e.g., a maximum resolving power of 240,000 (FWHM at m/z 200), excellent sub-ppm mass accuracy, and retrospective data analysis after data acquisition). Anti-doping practitioners are encouraged to take full advantage of the updated techniques of chromatography-mass spectrometry to develop sensitive, specific, and rapid screening methods for AASs. A new method for screening a wide range of AASs in human urine using GC-Orbitrap-HRMS was developed and validated. The method can qualitatively determine 70 anabolic androgenic steroids according to the minimum required performance limit of the World Anti-Doping Agency. Moreover, the validated method was successfully applied to detect six metabolites in urine after the oral administration of metandienone, and their excretion curves in vivo were studied. Metandienone M6 (17ß-hydroxymethyl-17α-methyl-18-nor-androst-1,4,13-trien-3-one) has been identified as a long-term urinary metabolite which can be detected up to 7 weeks, thus providing a longer detection window compared with previous studies. This study provides a rationale for GC-Orbitrap-HRMS in drug metabolism and non-targeted screening.

Signaling pathways in uric acid homeostasis and gout: From pathogenesis to therapeutic interventions.

Uric acid is a product of purine degradation, and uric acid may have multiple physiologic roles, including the beneficial effects as an antioxidant and neuroprotector, maintenance of blood pressure during low salt ingestion, and modulation of immunity. However, overproduction of metabolic uric acid, and/or imbalance of renal uric acid secretion and reabsorption, and/or underexcretion of extrarenal uric acid, e.g. gut, will contribute to hyperuricemia, which is a common metabolic disease. Long-lasting hyperuricemia can induce the formation and deposition of monosodium urate (MSU) crystals within the joints and periarticular structures. MSU crystals further induce an acute, intensely painful, and sterile inflammation conditions named as gout by NLRP3 inflammasome-mediated cleavage of pro-IL-1ß to bioactive IL-1ß. Moreover, hyperuricemia and gout are associated with multiple cardiovascular and renal disorders, e.g., hypertension, myocardial infarction, stroke, obesity, hyperlipidemia, type 2 diabetes mellitus and chronic kidney disease. Although great efforts have been made by scientists of modern medicine, however, modern therapeutic strategies with a single target are difficult to exert long-term positive effects, and even some of these agents have severe adverse effects. The Chinese have used the ancient classic prescriptions of traditional Chinese medicine (TCM) to treat metabolic diseases, including gout, by multiple targets, for more than 2200 years. In this review, we discuss the current understanding of urate homeostasis, the pathogenesis of hyperuricemia and gout, and both modern medicine and TCM strategies for this commonly metabolic disorder. We hope these will provide the good references for treating hyperuricemia and gout.

Fatty acid-binding proteins 3, 7, and 8 bind cholesterol and facilitate its egress from lysosomes.

Cholesterol from low-density lipoprotein (LDL) can be transported to many organelle membranes by non-vesicular mechanisms involving sterol transfer proteins (STPs). Fatty acid-binding protein (FABP) 7 was identified in our previous study searching for new regulators of intracellular cholesterol trafficking. Whether FABP7 is a bona fide STP remains unknown. Here, we found that FABP7 deficiency resulted in the accumulation of LDL-derived cholesterol in lysosomes and reduced cholesterol levels on the plasma membrane. A crystal structure of human FABP7 protein in complex with cholesterol was resolved at 2.7 Å resolution. In vitro, FABP7 efficiently transported the cholesterol analog dehydroergosterol between the liposomes. Further, the silencing of FABP3 and 8, which belong to the same family as FABP7, caused robust cholesterol accumulation in lysosomes. These two FABP proteins could transport dehydroergosterol in vitro as well. Collectively, our results suggest that FABP3, 7, and 8 are a new class of STPs mediating cholesterol egress from lysosomes.

Excessive iron deposition in root apoplast is involved in growth arrest of roots in response to low pH.

The rhizotoxicity of protons (H+) in acidic soils is a fundamental constraint that results in serious yield losses. However, the mechanisms underlying H+-mediated inhibition of root growth are poorly understood. In this study, we revealed that H+-induced root growth inhibition in Arabidopsis depends considerably on excessive iron deposition in the root apoplast. Reducing such aberrant iron deposition by decreasing the iron supply or disrupting the ferroxidases LOW PHOSPHATE ROOT 1 (LPR) and LPR2 attenuates the inhibitory effect of H+ on primary root growth efficiently. Further analysis showed that excessive iron deposition triggers a burst of highly reactive oxygen species, consequently impairing normal root development. Our study uncovered a valuable strategy for improving the ability of plants to tolerate H+ toxicity by manipulating iron availability.

Overview of role of survivin in cancer: expression, regulation, functions, and its potential as a therapeutic target.

Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.

Role of ideal cardiovascular health metrics in reducing risk of incident arrhythmias.

AIMS: Cardiovascular health (CVH) has been proven to reduce cardiovascular disease burden and mortality, but data are lacking regarding cardiac arrhythmias. The aim of this study was to assess the association between CVH metrics and atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS AND RESULTS: This study analysed data from the Atherosclerosis Risk in Communities (ARIC) cohort, with participants recruited from four different communities across the United States. Cardiovascular health metrics were scored at baseline (1987-89) following the American Heart Association's recommendations and categorized as poor, intermediate, or ideal. Arrhythmia episodes were diagnosed by International Classification of Diseases (ICD)-9 code. Adjusted associations were estimated using Cox models and event rates and population attributable fractions were calculated by CVH metrics category. The study population consisted of 13 078 participants, with 2548 AF, 1363 ventricular arrhythmias, and 706 bradyarrhythmias occurred. The adjusted hazard ratios (HRs) for ideal (vs. poor) CVH metrics were 0.59 [95% confidence interval (CI): 0.50-0.69] for AF, 0.38 (95% CI: 0.28-0.51) for ventricular arrhythmias, and 0.70 (95% CI: 0.51-0.97) for bradyarrhythmia. The risk of incident arrhythmias decreased steadily as the CVH metrics improved from 0 to 14 scores. The adjusted population attributable fractions were calculated to be 29.9% for AF, 54.4% for ventricular arrhythmias, and 21.9% for bradyarrhythmia, respectively. The association between CVH metrics and incident arrhythmias was also seen in people who remained free of coronary heart disease over the follow-up. CONCLUSION: Achieving ideal CVH metrics recommendations by AHA in midlife was associated with a lower risk of incident arrhythmias later in life.

Intermediate and ideal levels of cardiovascular health (CVH) metrics are associated with a markedly reduced risk of developing incident arrhythmias, including atrial fibrillation/flutter, ventricular arrhythmias, and bradyarrhythmia, independent of coronary heart disease. A majority of incident arrhythmias could be prevented if the risk profile of the entire population was optimized. These findings emphasize the significance of public health policies that improve CVH to reduce the social and economic burden of arrhythmias.

Higher Cumulative Blood Pressure in Midlife Predicts an Increased Risk of Atrial Fibrillation: Evidence From the Atherosclerosis Risk in Communities Study.

BACKGROUND: Elevated blood pressure (BP) is reportedly associated with an increased risk of atrial fibrillation (AF). However, the association between cumulative BP exposure in midlife and incident AF in mid-to-late life remains unclear. METHODS AND RESULTS: Participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study with 4 consecutive BP measurements and no prevalent AF at baseline were included. Cumulative BP was calculated as the area under the curve from visit 1 to visit 4. Incident AF was identified by study visit ECGs, hospital discharge codes, or death certificates. A total of 9892 participants were included (44.6% men and mean age 62.9±5.7 years at visit 4) with 1550 (15.7%) individuals who developed new-onset AF during an average follow-up of 15.4 years. The incidence rates of AF per 1000 person-years across the 4 quartiles of cumulative systolic BP were 7.9, 9.2, 12.5, and 16.9, respectively. After multivariable adjustment, the hazard ratios for incident AF among participants in the highest quartile of cumulative systolic BP, pulse pressure, and mean arterial pressure were 1.48 (95% CI, 1.27-1.72), 1.81 (95% CI, 1.53-2.13), and 1.22 (95% CI, 1.05-1.41), respectively, compared with those in the lowest quartile. The addition of cumulative systolic BP or pulse pressure slightly improved the ability to predict new-onset AF. CONCLUSIONS: Higher exposure to cumulative systolic BP, pulse pressure, and mean arterial pressure was significantly associated with increased risk of incident AF.

The pan-liver network theory: From traditional chinese medicine to western medicine.

In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.

Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma.

Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments. Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide. Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model. Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.

Identify GADD45G as a potential target of 4-methoxydalbergione in treatment of liver cancer: bioinformatics analysis and in vivo experiment.

BACKGROUND: The growth arrest and DNA damage-inducible gene gamma (GADD45G), an important member of GADD45 family, has been connected to the development of certain human cancers. Our previous studies have confirmed that GADD45G expression could be upregulated by 4-methoxydalbergione (4MOD) in liver cancer cells, but its potential pathological role in hepatocellular carcinoma (HCC) has not been fully understood. This study aimed to determine potential role of GADD45G in HCC, and the effects of 4-methoxydalbergione (4MOD) on the regulation of GADD45G expression in vivo were also analyzed. METHODS: Publicly available data and in-house immunohistochemistry (IHC) experiments were utilized to explore the expression profiles and clinical significance of GADD45G in HCC samples. Functional enrichment analysis based on GADD45G co-expression genes was used to excavate the molecular mechanism of GADD45G in HCC. We also conducted in vivo experiment on BALB/c nude mice to excavate the inhibitory effect of 4MOD on HCC and to evaluate the differences in the expression of GADD45G in xenograft tissues between the 4MOD-treated and untreated groups. RESULTS: GADD45G displayed significant low expression in HCC tissues. Downregulated expression of GADD45G was positively correlated with some high risk factors in HCC patients and predicted worse prognosis of HCC patients. There was a close association of GADD45G mRNA expression and immune cells, including neutrophils, NK cells, CD8 T cells, and macrophages. Co-expressed genes of GADD45G were involved in several pathways including cell cycle, carbon metabolism, and peroxisome. 4MOD could significantly suppress the growth of HCC in vivo, and this inhibitory effect was dependent on the upregulation of GADD45G expression. CONCLUSION: GADD45G expression can be used as a new clinical biomarker for HCC and GADD45G may be a potential target for the anti-cancer effect of 4MOD in liver cancer.

A single amino acid substitution in the capsid protein of Zika virus contributes to a neurovirulent phenotype.

Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins.

Development and Validation of a Risk Nomogram Model for Predicting Constipation in Patients with Type 2 Diabetes Mellitus.

Purpose: Constipation is a common complication of diabetic patients, which has a negative impact on their own health. This study aims to establish and internally validate the risk nomogram of constipation in patients with type 2 diabetes mellitus (T2DM) and to test its predictive ability. Patients and Methods: This retrospective study included 746 patients with T2DM at two medical centers. Among the 746 patients with T2DM, 382 and 163 patients in the Beilun branch of the First Affiliated Hospital of Zhejiang University were enrolled in the training cohort and the validation cohort, respectively. A total of 201 patients in the First Affiliated Hospital of Nanchang University were enrolled in external validation cohorts. The nomogram was established by optimizing the predictive factors through univariate and multivariable logistic regression analysis. The prediction performance of the nomogram was measured by the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA). Furthermore, its applicability was internally and independently validated. Results: Among the 16 clinicopathological features, five variables were selected to develop the prediction nomogram, including age, glycated hemoglobin (HbA1c), calcium, anxiety, and regular exercise. The nomogram revealed good discrimination with an area under the receiver operating characteristic curve (AUROC) of 0.908 (95% CI = 0.865-0.950) in the training cohort, and 0.867 (95% CI = 0.790-0.944) and 0.816 (95% CI = 0.751-0.881) in the internal and external validation cohorts, respectively. The calibration curve presented a good agreement between the prediction by the nomogram and the actual observation. The DCA revealed that the nomogram had a high clinical application value. Conclusion: In this study, the nomogram for pretreatment risk management of constipation in patients with T2DM was developed which could help in making timely personalized clinical decisions for different risk populations.

HFIST-Net: High-throughput fast iterative shrinkage thresholding network for accelerating MR image reconstruction.

BACKGROUND AND OBJECTIVES: Compressed sensing (CS) is often used to accelerate magnetic resonance image (MRI) reconstruction from undersampled k-space data. A novelty deeply unfolded networks (DUNs) based method, designed by unfolding a traditional CS-MRI optimization algorithm into deep networks, can provide significantly faster reconstruction speeds than traditional CS-MRI methods while improving image quality. METHODS: In this paper, we propose a High-Throughput Fast Iterative Shrinkage Thresholding Network (HFIST-Net) for reconstructing MR images from sparse measurements by combining traditional model-based CS techniques and data-driven deep learning methods. Specifically, the conventional Fast Iterative Shrinkage Thresholding Algorithm (FISTA) method is expanded as a deep network. To break the bottleneck of information transmission, a multi-channel fusion mechanism is proposed to improve the efficiency of information transmission between adjacent network stages. Moreover, a simple yet efficient channel attention block, called Gaussian context transformer (GCT), is proposed to improve the characterization capabilities of deep Convolutional Neural Network (CNN,) which utilizes Gaussian functions that satisfy preset relationships to achieve context feature excitation. RESULTS: T1 and T2 brain MR images from the FastMRI dataset are used to validate the performance of the proposed HFIST-Net. The qualitative and quantitative results showed that our method is superior to those compared state-of-the-art unfolded deep learning networks. CONCLUSIONS: The proposed HFIST-Net is capable of reconstructing more accurate MR image details from highly undersampled k-space data while maintaining fast computational speed.

Highly Specific Antibiotic Detection on Water-Stable Black Phosphorus Field-Effect Transistors.

Two-dimensional (2D) black phosphorus (BP) has been reported to have appealing semiconducting properties as the sensing channel in field-effect transistor (FET) sensors. However, the intrinsic instability of BP in water greatly hinders its application, and little is known about its sensing performance and mechanism in aqueous medium. Herein, a water-stable BP FET sensor for antibiotic detection is reported. A novel surface engineering strategy with Ag+ coordination and melamine cyanurate (MC) supramolecular passivation is utilized to enhance the stability and transistor performance of BP. With molecularly imprinted polymers (MIPs) as the detection probe for tetracycline, the BPAg(+)/MC/MIPs sensor shows high sensitivity to tetracycline with a detection limit of 7.94 nM and a quick response within 6 s as well as high selectivity against other antibiotics with similar molecular structures. A new sensing mechanism relying on the conjugation effect of the probe structure is proposed, and new knowledge about alkalinity-enhanced and ionic strength-related response from the electrostatic gating effect is given based on the solution chemistry impact study. This work offers an efficient surface engineering strategy to enable the application of 2D BP for antibiotic detection in aqueous medium and presents a new sensing mechanism in chemical analysis by FET sensors.

Fluorescence Detection of Trace Disinfection Byproducts by Ag Nanoprism-Modulated Lanthanide MOFs.

Disinfection byproducts (DBPs), as an emerging water pollutant, present increasing concern and risk in public health and water safety. Due to their low concentration levels and inherent similarity in molecular structures, sensitive and accurate determination of DBPs is still a challenge especially for onsite or online detection. Herein, a self-regulated fluorescent probe based on the Ag nanoprism-modified lanthanide metal-organic framework (AgNPR@EuMOF) is designed for trichloroacetic acid (TCAA) detection. The EuMOF is constructed with Eu as the metal node and 5-boronoisophthalic acid as the ligand. By introducing sulfhydryl groups into EuMOF, AgNPR can be anchored on the EuMOF surface through Ag-S bonds, enabling the synthesis of stable AgNPR@EuMOF composites. During the sensing process, the triangle AgNPR will react with the organic halogen molecule, accomplished with the blue shift of surface plasmon resonance absorption peak and the significant change in the fluorescence of EuMOF. This probe can detect TCAA in a wide concentration range (0.1-40 µM) with high sensitivity and specificity. The density functional theory calculation on binding energies between DBPs and AgNPR suggests that TCAA has the largest interaction ability with AgNPR than other DBPs. Moreover, the detection of TCAA in real tap water and swimming pool water is also demonstrated with high accuracy. The reported AgNPR@EuMOF represents one of the pioneer fluorescence probes in DBP detection, which holds great promise for onsite or online analysis of trace DBPs in water.

Transauricular Vagal Nerve Stimulation at 40 Hz Inhibits Hippocampal P2X7R/NLRP3/Caspase-1 Signaling and Improves Spatial Learning and Memory in 6-Month-Old APP/PS1 Mice.

OBJECTIVES: Transauricular vagal nerve stimulation (taVNS) at 40 Hz attenuates hippocampal amyloid load in 6-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, but it is unclear whether 40-Hz taVNS can improve cognition in these mice. Moreover, the underlying mechanisms are still unclear. MATERIALS AND METHODS: 6-month-old C57BL/6 (wild type [WT]) and APP/PS1 mice were subjected to 40-Hz taVNS. Novel Object Recognition and the Morris Water Maze were used to evaluate cognition. Hippocampal amyloid-ß (Aß)1-40, Aß1-42, pro-interleukin (IL)-1ß, and pro-IL-18 were measured using enzyme-linked immunosorbent assays. Hippocampal Aß42, purinergic 2X7 receptor (P2X7R), nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3), Caspase-1, IL-1ß, and IL-18 expression were evaluated by western blotting. Histologic assessments including immunofluorescence, immunohistochemistry, Nissl staining, and Congo red staining were used to assess microglial phagocytosis, neuroprotective effects, and Aß plaque load. RESULTS: 40-Hz taVNS improved spatial memory and learning in 6-month-old APP/PS1 mice but did not affect recognition memory. There were no effects on the cognitive behaviors of 6-month-old WT mice. taVNS at 40 Hz modulated microglia; significantly decreased levels of Aß1-40, Aß1-42, pro-IL-1ß, and pro-IL-18; inhibited Aß42, P2X7R, NLRP3, Caspase-1, IL-1ß, and IL-18 expression; reduced Aß deposits; and had neuroprotective effects in the hippocampus of 6-month-old APP/PS1 mice. These changes were not observed in 6-month-old WT mice. CONCLUSION: Our results show that 40-Hz taVNS inhibits the hippocampal P2X7R/NLRP3/Caspase-1 signaling and improves spatial learning and memory in 6-month-old APP/PS1 mice.