Clemastine improves emotional and social deficits in adolescent social isolation mice by reversing demyelination.

Adolescence is a critical period for social experience-dependent oligodendrocyte maturation and myelination. Adolescent stress predisposes to cause irreversible changes in brain structure and function with lasting effects on adulthood or beyond. However, the molecular mechanisms linking adolescent social isolation stress with emotional and social competence remain largely unknown. In our study, we found that social isolation during adolescence leads to anxiety-like behaviors, depression-like behaviors, impaired social memory and altered patterns of social ultrasonic vocalizations in mice. In addition, adolescent social isolation stress induces demyelination in the prefrontal cortex and hippocampus of mice, with decreased myelin-related gene expression and disrupted myelin structure. More importantly, clemastine was sufficient to rescue the impairment of emotional and social memory by promoting remyelination. These findings reveal the demyelination mechanism of emotional and social deficits caused by social isolation stress in adolescence, and provides potential therapeutic targets for treating stress-related mental disorders.

Theoretical study on optimizing dipeptidomimetic isocyanonaphthalene chemosensor and the fluorescence mechanism for detecting Hg2.

The excited (S1) state charge distribution characteristics and fluorescence mechanism of fluorescence probes benzyl (6-cyano-2-naphthoyl)-L-valinate (NPI) and benzyl (6-amino-2-naphthoyl)-L-valinate (NPA) have been discussed using density functional theory (DFT) and time-dependent density functional theory (TD-DFT). Further analysis by constructing a torsional potential energy curve (PEC) shows that a well-defined minimum energy conformation is observed when the C-C single bond between the valine benzyl ester and naphthalene ring in NPI rotates. For NPA, the most stable conformation is the naphthalene ring conformation with dihedral angle N2C1C2C3 of -30.60°, whose total energy is 0.17 kcal/mol lower than that of the second most stable conformer. The frontier molecular orbitals (FMOs) demonstrate that NPI exhibits a low degree of charge coupling, and the oscillator intensity is close to zero, indicating that it is not conducive to luminescence. However, in the S1 state, the oscillator strength of NPA is 1.2044, which is a bright state, resulting in the strong emitting. Additionally, fluorescence imaging is favored as a visual observation technique, and Stokes shift is an important physical parameter to measure fluorescence. According to the idea that changing the number and position of functional groups can affect the photophysical properties of fluorescent dyes, o-NPDI, p-NPDI and m-NPDI dyes were newly designed and o-NPDA, p-NPDA, m-NPDA produced after recognition of Hg2+. The spectral performance results show that the newly designed fluorescent dye (p-NPDA) can not only emit in the near infrared region after recognizing Hg2+, but also has a large Stokes shift (236 nm). This indirectly reflects that para-substitution is more conducive to Stokes shift, and has become one of the strategies for fluorescent dye design.

Value of circulating tumor cell assisting low-dose computed tomography in screening pulmonary nodules based on existing liquid biopsy techniques: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: This study aims to assess the diagnostic utility of circulating tumor cells (CTCs) in conjunction with low-dose computed tomography (LDCT) for differentiating between benign and malignant pulmonary nodules and to substantiate the foundation for their integration into clinical practice. METHODS: A systematic literature review was performed independently by two researchers utilizing databases including PubMed, Web of Science, The Cochrane Library, Embase, and Medline, to collate studies up to September 15, 2023, that investigated the application of CTCs in diagnosing pulmonary nodules. A meta-analysis was executed employing Stata 15.0 and Revman 5.4 to calculate the pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curve (AUC). Additionally, trial sequential analysis was conducted using dedicated TSA software. RESULTS: The selection criteria identified 16 studies, encompassing a total of 3409 patients. The meta-analysis revealed that CTCs achieved a pooled sensitivity of 0.84 (95% CI 0.80 to 0.87), specificity of 0.80 (95% CI 0.73 to 0.86), PLR of 4.23 (95% CI 3.12 to 5.72), NLR of 0.20 (95% CI 0.16 to 0.25), DOR of 20.92 (95% CI 13.52 to 32.36), and AUC of 0.89 (95% CI 0.86 to 0.93). CONCLUSIONS: Circulating tumor cells demonstrate substantial diagnostic accuracy in distinguishing benign from malignant pulmonary nodules. The incorporation of CTCs into the diagnostic protocol can significantly augment the diagnostic efficacy of LDCT in screening for malignant lung diseases.

Analysis of clinical risk factors for metabolic bone disease of prematurity.

Objective: To analyze clinical data related to preterm infants and identify risk factors for metabolic bone disease of prematurity (MBDP). Methods: This study involved 856 newborns with a gestational age of less than 37 weeks or a weight of less than 1,500g at the Second Hospital of Jilin University. Multifactorial analysis was performed using logistic regression models to explore the risk factors for MBDP. Linear regression was used to investigate the factors affecting the time of alkaline phosphatase (ALP) exceedance and the peak value of ALP in the MBDP group. Results: In the MBDP group, ALP excesses occurred in preterm infants at an average of 39.33 days after birth, and the mean value of peak ALP was 691.41 IU/L. Parenteral nutrition and the application of assisted ventilation were independent risk factors for MBDP, with ORs of 1.02 and 1.03 respectively. Gestational age was found to be a protective factor for earlier time of onset of ALP exceedance (ß = 2.24,) and the increase in the peak value of ALP (ß = -16.30). Conclusion: Parenteral nutrition and the application of assisted ventilation are independent risk factors for MBDP. Gestational age is a major factor influencing the time of onset of ALP exceedance and the peak value of ALP in infants with MBDP.

Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.

Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings. Antisense oligonucleotides (ASOs) have also been investigated for oral administration but despite the recent progress, the bioavailability remains low. Given the advancement with highly potent and durable trivalent N-acetylgalactosamine (GalNAc)-conjugated small interfering RNAs (siRNAs) via subcutaneous (s.c.) injection, we explored their activities after oral administration. We report robust RNA interference (RNAi) activity of orally administrated GalNAc-siRNAs co-formulated with permeation enhancers (PEs) in rodents and non-human primates (NHPs). The relative bioavailability calculated from NHP liver exposure was <2.0% despite minimal enzymatic degradation in the GI. To investigate the impact of oligonucleotide size on oral delivery, highly specific GalNAc-conjugated single-stranded oligonucleotides known as REVERSIRs with different lengths were employed and their activities for reversal of RNAi effect were monitored. Our data suggests that intestinal permeability is highly influenced by the size of oligonucleotides. Further improvements in the potency of siRNA and PE could make oral delivery of GalNAc-siRNAs as a practical solution.

Polymer-Unit Graph: Advancing Interpretability in Graph Neural Network Machine Learning for Organic Polymer Semiconductor Materials.

The graph representation of complex materials plays a crucial role in the field of inorganic and organic materials investigations for developing data-centric materials science, such as those using graph neural networks (GNNs). However, the currently prevalent GNN models are primarily employed for investigating periodic crystals and organic small molecule data, yet they still encounter challenges in terms of interpretability and computational efficiency when applied to polymer monomers and organic macromolecules data. There is still a lack of graph representation of organic polymers and macromolecules specifically tailored for GNN models to explore the structural characteristics. The Polymer-unit Graph, a novel coarse-grained graph representation method introduced in study, is dedicated to expressing and analyzing polymers and macromolecules. By incorporating the Polymer-unit Graph into the GNN models and analyzing the organic semiconductor (OSC) materials database, it becomes possible to uncover intricate structure-property relationships involving branched-chain engineering, fluoridation substitution, and donor-acceptor combination effects on the elementary structure of OSC polymers. Furthermore, the Polymer-unit Graph enables visualizing the relationship between target properties and polymer units while reducing training time by an impressive 98% and minimizing molecular graph representation models. In conclusion, the Polymer-unit Graph successfully integrates the concept of Polymer-unit into the field of GNNs, enabling more accurate analysis and understanding of organic polymers and macromolecules.

Theoretical investigation on regulating photophysical properties and proton transfer behavior by electronegativity for near-infrared emitting styryl dyes.

Our main focus is to explore the atomic electronegativity-dependent photoinduced behavior of styryl derivatives (HBO, HBS, and HBSe). The results of structural parameter calculation by the DFT method show that the intramolecular hydrogen bonds of normal and tautomer form are strengthened and weakened, respectively, in an excited state (S1), which is conducive to the excited intramolecular proton transfer (ESIPT) process. The enhancement of excited hydrogen bond is beneficial to the ESIPT process from the aspects of infrared vibration frequency (IR), Mulliken's charge analysis, and density gradient reduction (RDG). Additionally, by determining the bond energy with the band critical point (BCP) parameter, we found that the lower the electronegativity of the atom, the larger the hydrogen bond strength at the excited state and the more likely ESIPT reaction occurs. Meanwhile, the intramolecular H-bonds O-H…N in HBO, HBS, and HBSe are enhanced with the weakened electron-withdrawing capacity of the atom (from O to S and Se). Subsequently, frontier molecular orbital (FMOs) and charge density difference (CDD) analyses essentially revealed that electron redistribution induces the ESIPT process. Low atomic electronegativity exhibits the high chemical activity of the excited state. Furthermore, to demonstrate the electronegativity-dependent ESIPT behavior of the system, we built potential energy curves (PECs) and located the transition states (TS) of proton transfer processes.

Anthocyanin and proanthocyanidin from Aronia melanocarpa (Michx.) Ell.: Purification, fractionation, and enzyme inhibition.

Aronia melanocarpa (Michx.) Ell. is a rich source of anthocyanins and proanthocyanidins with confirmed health benefits. Individual cyanidin glucosides (cyanidin 3-galactoside, cyanidin 3-arabinoside, cyanidin 3-xyloside, and cyanidin 3-glucoside) of anthocyanins (calculated by individual cyanin glycoside fractions was 419.9 mg/100 g FW) were isolated by Sephadex LH-20 column and different parts of proanthocyanidins with a different mean degree of polymerization (mDP) were fractionated by the solubility differences in different solvents. The composition of different mDP of proanthocyanidins was as follows: monomers (1.51%), oligomer (mDP of 4.2 ± 0.9, 20.57%), CPP-50 (mDP of 78.9 ± 4.1, 22.17%), CPP-60 (mDP of 66.1 ± 1.2, 27.94%), CPP-70 (mDP of 36.8 ± 3.9, 36.8%), CPP-75 (mDP of 25.2 ± 1.3, 6.14%), CPP-L (mDP of 10.2 ± 2.6, 6.95%), and there were recycling loss of 0.34%. Cyanidin 3-glucoside showed the strongest inhibition effects on α-amylase and lipase and cyanidin 3-arabinoside showed the strongest inhibition effect on α-glucosidase, while cyanidin 3-xyloside has no inhibition effect on the α-amylase, and cyanidin 3-galactoside, cyanidin 3-arabinoside, and cyanidin 3-xyloside have no inhibition effects on lipase. The inhibition effect of proanthocyanidins with different mDP to the enzymes all showed high negative correlations between the mDP and IC50 (half-maximal inhibitory concentration). This study suggests that A. melanocarpa (Michx.) Ell. can have beneficial effects due to inhibition of the digestion enzyme.

Use of Carbon Nanoparticles to Improve the Efficiency of Harvesting Lymph Nodes in Rectal Cancer.

BACKGROUND: The accurate determination of lymph node status in patients with rectal cancer requires harvesting a certain number of lymph nodes. This study investigated whether using carbon nanoparticles (CNs) could improve the efficiency of harvesting lymph nodes in rectal cancer patients. MATERIALS AND METHODS: Data from patients with rectal cancer treated with radical resection were collected from Nanfang Hospital between January 2014 and June 2021. Patients in the CN group received a CN suspension 1 day before surgery, which was endoscopically injected around the tumor. A 1:1 case-matched study was performed using the propensity score. The efficiency of harvesting lymph nodes was investigated by comparing the number of total nodes, total time, and percentage of nodes <5 mm in size between the CN and non-CN groups. RESULTS: A total of 768 patients were included, with 246 patients who underwent CN injection and 522 patients who did not. After matching, 246 pairs of patients were analyzed. After matching, the number of total nodes of each sample was significantly higher in the CN group than in the non-CN group ( P <0.001). The total time for node detection ( P <0.001) was significantly shorter in the CN group. The percentage of nodes <5 mm in size was increased significantly in the CN group ( P <0.001). Among patients with clinical staging I/II, the difference in positive LNs was significant (21.79% vs. 11.95%, P =0.029). CONCLUSIONS: The application of CNs improved the efficiency of harvesting lymph nodes during rectal cancer surgery.

Investigation on non-radioactive behavior of an acylhydrazone-based fluorescent probe: Coexistence of PET and TICT mechanisms.

A fluorescent probe (E)-((2,4-dihydroxybenzyl)diazenyl)(pyridin-2-yl)methanone (HL) to effectively and selectively detect Al3+ was designed and synthesized in the experiment. Herein, we explained the excited state dynamics mechanism of HL by using density functional theory (DFT) and time-dependent density functional theory (TD-DFT). The potential energy surfaces (PESs) proved that the excited-state intramolecular proton transfer (ESIPT) process hardly occurs due to the high reaction barriers, so the fluorescence quenching behavior of HL was not based on ESIPT. The frontier molecular orbitals (FMOs) and spectral properties were analyzed to better understand the origination of fluorescence quenching. It was found that an electron on C = N in HL could be transferred to the fluorophore during excitation in the absence of Al3+, accompanied by the PET process. The excited state could undergo a twisted intramolecular charge transfer (TICT) process, releasing non-radiative decay. After binding to Al3+, the photo-induced electron transfer (PET) process has no longer occurred, and the TICT process is eliminated, resulting in a significant fluorescence enhancement. Therefore, the calculation results well explain the quenching and enhancement behaviors of fluorescence before and after the reaction with Al3+.

Yin Huo Tang, a traditional Chinese herbal formula, relives ovariectomy and empty bottle stimulation-induced menopause-like symptoms in mice.

Background: Yin Huo Tang (YHT), a traditional Chinese herbal formula, is effectively used for the clinical treatment of menopause-like symptoms in China. This study aimed to investigate its efficacy on menopause-like symptoms in mice using behavioral tests and histopathological assessment, and to determine its possible mechanism of action based on network pharmacology. Methods: Liquid chromatography-mass spectrometry (LC-MS) technology was used to identify the potential active ingredients of YHT. In mice, menopause-like symptoms were induced by combination of bilateral ovariectomy and empty bottle stimulation. The mice were then treated with the YHT aqueous extract for three weeks. Behavior, sleep state, body weight, organ index, and histomorphology were analyzed separately. Additionally, network pharmacology and molecular docking were used to predict the mechanisms underlying the action of YHT. Finally, serum estradiol was quantified to preliminarily verify the results of network pharmacology. Results: YHT not only improved the behavior of mice (attack and explore behavior reduced; modify behavior increased) but also ameliorated the sleep state (sleep time increased and incubation time reduced). YHT reduced body weight, increased uterine weight, and improved the histomorphology of some organs. Network pharmacology and molecular docking analyses revealed that the estrogen signaling pathway might play a key role in attenuating menopause-like symptoms. Furthermore, YHT treatment reversed the reduction in serum estradiol levels. Conclusions: YHT alleviates menopause-like symptoms in a mouse model, providing a rationale for using it as a potential therapeutic strategy.

Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics.

At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule and biologics guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in its physicochemical, absorption, distribution, metabolism and excretion properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the 'siRNA working group' in the IQ Consortium compile a list of reports included in approved siRNA filing packages and discuss the relevance of two in vitro reports-the plasma protein binding evaluation and the drug-drug interaction risk assessment-to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA plasma protein binding and drug-drug interactions in understanding pharmacokinetic/pharmacodynamic relationships, safety and translation. The findings are summarized into two decision trees to help guide industry decide when in vitro siRNA plasma protein binding and drug-drug interaction studies are warranted.

Effects of five extraction methods on total content, composition, and stability of flavonoids in jujube.

The present study investigated the effects of different extraction methods including water-water bath (W-WB), ethanol-water bath (E-WB), deep eutectic solvent (DES) combined with ultrasound-assisted extraction (DES-UAE), microwave-assisted extraction (DES-MAE), and enzyme-assisted extraction (DES-EAE) on flavonoids (total flavonoid content, flavonoid composition, and stability) in jujube. The highest total flavonoid content of 8.03 mg/g was obtained by the DES-MAE extraction. Fifteen types of flavonoids were identified from jujube. The amount of rutin produced by the E-WB and DES-UAE methods was 66.88 ± 1.58 µg/g and 45.23 ± 3.22 µg/g, respectively. The retention of flavonoids in DES-UAE extracts were 98.15 ± 0.51%, 64.25 ± 2.21% after 2 h of high temperature treatment at 90 °C and 21 days of dark storage, respectively. The flavonoids extracted by different methods were suitable for dark storage under different light contrasts, where the retention of flavonoids extracted by DES-UAE method was 86.44 ± 2.45%. In conclusion, DES-UAE would be an efficient method for flavonoid extraction from jujube.

MicroRNA-625-3p improved proliferation and involved chemotherapy resistance via targeting PTEN in high grade ovarian serous carcinoma.

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) is an aggressive gynaecological malignancy and associated with poor prognosis. Here we examined the effects of miR-625-3p on proliferation, treatment, migration and invasion in HGSOC. METHODS: The proliferation of HGSOC cells was evaluated by MTT assay. Transwell assay was performed to examine migration and matrigel assay were used to assess invasion. The effect of miR-625-3p on cisplatin-induced apoptosis was investigated by Caspase-Glo3/7 assay. The dual-luciferase reporter assay was carried out to confirm the potential binding site. RESULTS: Overexpression of miR-625-3p promoted proliferation, and increased migration and invasion in HGSOC cells. MiR-625-3p significantly inhibited cisplatin sensitivity in HGSOC cells. Meanwhile, miR-625-3p decreased cisplatin-induced apoptosis by regulation of BAX and Bcl-2 expression. Furthermore, aberrant expression of miR-625-3p changed PTEN expression by directly binding to 3'UTR of PTEN. Further study showed miR-625-3p expression was higher in human HGSOC tissue than normal ovarian tissues and associated with higher clinical stage. CONCLUSIONS: miR-625-3p promotes HGSOC growth, involves chemotherapy resistance and might serve as a potential biomarker to predict chemotherapy response and prognosis in HGSOC.

The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human.

Conjugation of oligonucleotide therapeutics, including small interfering RNAs (siRNAs) or antisense oligonucleotides, to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI (givosiran) for the treatment of acute hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio (inclisiran) for the treatment of hypercholesterolemia, the technology has been well validated clinically. Although much knowledge has been gained over decades of development, there is a paucity of published literature on the drug metabolism and pharmacokinetic properties of GalNAc-siRNA. With this in mind, the goals of this minireview are to provide an aggregate analysis of these nonclinical absorption, distribution, metabolism, and excretion (ADME) data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through asialoglycoprotein receptor-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex in hepatocytes, are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the ADME properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, are largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. SIGNIFICANCE STATEMENT: Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the pharmacokinetic/pharmacodynamic translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species, building confidence in the ability to extrapolate to human.

MicroRNA-100 Enhances Autophagy and Suppresses Migration and Invasion of Renal Cell Carcinoma Cells via Disruption of NOX4-Dependent mTOR Pathway.

Renal cell carcinoma (RCC) is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy. Recently, microRNAs (miRNAs or miRs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. In the present study, we aim to explore the potential role of miR-100 in RCC by targeting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) through the mammalian target of rapamycin (mTOR) pathway. Initially, microarray-based gene expression profiling of RCC was used to identify differentially expressed genes. Next, the expression of miR-100 and NOX4 was examined in RCC tissues and cell lines. Then, the interaction between miR-100 and NOX4 was identified using bioinformatics analysis and dual-luciferase reporter assay. Gain-of-function or loss-of-function approaches were adopted to manipulate miR-100 and NOX4 in order to explore the functional roles in RCC. The results revealed the presence of an upregulated NOX4 and a downregulated miR-100 in both RCC tissues and cell lines. NOX4 was verified as a target of miR-100 in cells. In addition, overexpression of miR-100 or NOX4 silencing could increase autophagy while decreasing the expression of mTOR pathway-related genes and migration and invasion. Conjointly, upregulated miR-100 can potentially increase the autophagy and inhibit the invasion and migration of RCC cells by targeting NOX4 and inactivating the mTOR pathway, which contributes to an extensive understanding of RCC and may provide novel therapeutic options for this disease.

In vivo real-time assessment of the anastomotic blood supply in colorectal surgery using confocal laser endomicroscopy in an anastomotic model.

BACKGROUND AND STUDY AIMS: Anastomotic ischemia can affect healing and eventually lead to anastomotic leakage, and confocal laser endomicroscopy (CLE) can offer detailed observations at the subcellular level. We aimed to evaluate the anastomotic microcirculation in different anastomotic perfusion models using CLE. METHODS: Anastomotic perfusion models were established using twelve rabbits distributed into two groups: group A (good perfusion, n = 6) and group B (poor perfusion, n = 6). Afterward, intraoperative detection of anastomotic perfusion was carried out using CLE, and quantitative analysis of blood cells was performed. Rabbits that satisfied the criteria underwent a second exploratory operation and specimens were stained by hematoxylin and eosin. RESULTS: Enhanced with fluorescein sodium, capillaries were obviously highlighted in group A, while few capillaries were viewed in group B. Delayed development of fluorescence occurred in group B. The average flow of blood cells was 37.0 ± 5.93 per minute in group A and 6.33 ± 2.16 per minute in group B (p < 0.001). In addition, during the second exploratory surgery, rabbits with inadequate anastomotic perfusion exhibited more serious intestinal adhesion and ischemia. Anastomotic leakage and abdominal infection occurred in all rabbits in group B. CONCLUSION: CLE can realize real-time imaging of the anastomotic microcirculation and is a feasible technique for performing intraoperative evaluation in different anastomotic perfusion situations. This animal experiment provides the groundwork for future in vivo research in humans.

Screening of characteristic genes in ulcerative colitis by integrating gene expression profiles.

BACKGROUND: This study aimed to screen the feature modules and characteristic genes related to ulcerative colitis (UC) and construct a support vector machine (SVM) classifier to distinguish UC patients. METHODS: Four datasets that contained UC and control samples were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) with consistency were screened via the MetaDE method. The weighted gene coexpression network (WGCNA) was used to distinguish significant modules based on the four datasets. The protein-protein interaction network was established based on intersection genes. Enrichment analysis of Gene Ontology (GO) biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were established based on DAVID. An SVM combined with recursive feature elimination was also applied to construct a disease classifier for the disease diagnosis of UC patients. The efficacy of the SVM classifier was evaluated through receiver operating characteristic curves. RESULTS: Twelve highly preserved modules were obtained using the WGCNA, and 2009 DEGs with significant consistency were selected using the MetaDE method. Sixteen significantly related GO BPs and 12 KEGG pathways were obtained, such as cytokine-cytokine receptor interaction, cell adhesion molecules, and leukocyte transendothelial migration. Subsequently, 41 genes were used to construct an SVM classifier, such as CXCL1, CCR2, IL1B, and IL1A. The area under the curve (AUC) was 0.999 in the training dataset, whereas the AUC was 0.886, 0.790, and 0.819 in the validation set (GSE65114, GSE37283, and GSE36807, respectively). CONCLUSIONS: An SVM classifier based on feature genes might correctly identify healthy people or UC patients.

Silibinin ameliorates depression/anxiety-like behaviors of Parkinson's disease mouse model and is associated with attenuated STING-IRF3-IFN-ß pathway activation and neuroinflammation.

Depression and anxiety are common neuropsychiatric symptom of Parkinson's disease (PD), reflecting reduced quality of life in patients with PD. Silibinin (silybin), a flavonoid extracted and isolated from the fruit of Silybum marianum (L.) Gaertn, is widely used for the treatment of hepatic diseases. We report here that silibinin shows anti-depressant and anti-anxiety effects on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model mice with PD. All the results of open field test, elevated plus maze test, tail suspension test and forced swimming test demonstrated that silibinin administration significantly attenuated MPTP-induced depression/anxiety. Hematoxylin-eosin (HE) staining and Nissl staining results showed that MPTP injection caused the damage of hippocampal neurons, but this was ameliorated by oral administration of silibinin. Silibinin significantly restored hippocampal levels of 5-hydroxyptramine (5-HT) and noradrenaline (NA), two important neurotransmitters for regulating mood, which decreased in MPTP-injected mice. Neuroinflammation, as reflected by the increased expressions of IL-1ß, TNFα and IFN-ß, was marked in the hippocampus of MPTP-treated mice, accompanying increased stimulator of interferon genes (STING) and interferon regulatory factor-3 (IRF3). Silibinin administration, however, down-regulated the levels of IL-1ß, TNFα and IFN-ß, as well as STING and IRF3, protecting MPTP-induced PD model mice. These findings indicate that silibinin has a potential of being further developed as a therapeutic for depression and anxiety in PD.

The Prognostic Value of Left Ventricular Mechanical Dyssynchrony Derived from Cardiac MRI in Patients with Idiopathic Dilated Cardiomyopathy.

PURPOSE: To investigate the prognostic value of mechanical dyssynchrony evaluated by deformable registration algorithm (DRA) analysis of cardiac MRI (CMR) in patients with idiopathic dilated cardiomyopathy (DCM). MATERIALS AND METHODS: This secondary analysis of a prospective study (clinical trial no. ChiCTR1800017058) enrolled 409 patients (mean age, 48 years ± 14:300 men) with idiopathic DCM who underwent CMR between June 2012 and September 2018. Mechanical dyssynchrony was measured as standard deviation of time-to-peak (sdTTP) and uniformity ratio estimate (URE) indexes by DRA strain analysis. The primary endpoint included all-cause mortality and heart transplantation. The secondary endpoint included primary endpoint, aborted sudden cardiac death, and heart failure readmission. Cox regression analyses and Kaplan-Meier survival analysis were performed to identify the association between variables and outcomes. RESULTS: During a median follow-up of 25.1 months, 57 and 132 patients reached primary and secondary endpoints, respectively. Most URE indexes were significantly lower in patients reaching primary endpoint. In multivariable analysis, circumferential URE (CURE) at apical level was independently associated with primary endpoints (hazard ratio, 0.307 [95% CI: 0.106, 0.883]; P = .03) and secondary endpoints (hazard ratio, 0.452 [95% CI: 0.209, 0.979]; P = .04), whereas most sdTTP measures were not. Furthermore, among patients with left ventricular ejection fraction of less than 35% or presence of late gadolinium enhancement, those with CURE at apical level of less than 0.917 had a significantly higher rate of adverse outcomes. CONCLUSION: URE indexes were more predictive of prognostic outcomes compared with sdTTP measurements; the CURE at apical level was an independent predictor of adverse cardiac events in patients with DCM.Keywords: Heart, Outcomes Analysis, MR-ImagingClinical trial registration no. ChiCTR1800017058 Supplemental material is available for this article. See also commentary by Rajiah and François in this issue.© RSNA, 2021.