Integrated single-cell and bulk RNA sequencing reveals CREM is involved in the pathogenesis of ulcerative colitis.

Background: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by persistent colonic inflammation. Here, we performed a systematic analysis to gain better insights into UC pathogenesis. Methods: We analyzed two UC-related datasets extracted from the gene expression omnibus database using several bioinformatics tools. The primary cell types and key subgroups of primary cells associated with UC and differentially expressed genes (DEGs) between UC and control samples were identified. The molecular regulation of the key genes was also predicted. The gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses of marker genes of key cell subgroups and model genes were performed. The expression of key enriched genes was validated in 10 clinical samples using real-time quantitative polymerase chain reaction (RT-qPCR). Results: Monocytes were identified as the major cell type. Ten differentially expressed marker genes were obtained by intersecting the 3121 DEGs, 38 marker genes in major cell types, and 104 marker genes in key cell subgroups. Four essential genes, associated with immune response, were obtained using support vector machine recursive feature elimination and least absolute shrinkage and selection operator analyses. The four essential genes were highly expressed in Cluster 0 during differentiation. Validation of the four key genes in colonic mucosal biopsy specimens from 10 normal and 10 UC patients revealed that CREM was highly expressed in both the lesion-free sites and lesion sites colonic mucosa of UC patients compared with normal adults. Conclusions: We identified CREM involved in UC pathogenesis, which is expected to provide a new therapeutic target for UC.

The Therapeutic Mechanisms of Shenyan Oral Liquid I Against Chronic Kidney Disease Based on Network Pharmacology and Experimental Validation.

BACKGROUND: Chronic Kidney Disease (CKD) leads to structural and functional abnormalities of the kidneys and seriously jeopardizes human health. Shenyan Oral Liquid (SOLI), a Chinese medicinal preparation, has been reported to protect podocytes in patients with chronic kidney disease (CKD). OBJECTIVE: The objective of this study is to investigate the mechanism of action of the Chinese medicinal preparation Senyan Oral Liquid (SOLI) in the treatment of CKD by protecting podocytes through network pharmacology technology and experimental validation. METHODS: Compounds of SOLI and targets of CKD disease were collected and screened. The SOLI network of bioactive compounds targeting CKD and the protein-protein interaction (PPI) network were constructed using Cytoscape software and the STRING online database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R software Cluster Profiler package. Molecular docking was performed using Autodock software to verify the binding ability of bioactive compounds and target genes. Subsequently, the potential mechanism of SOLI on CKD predicted by network pharmacological analysis was experimentally studied and verified in an adriamycin-induced nephropathy rat model. RESULTS: A total of 81 targets of SOLI components acting on CKD were identified. The results of the PPI analysis clarified that five key target genes (TNF, AKT1, IL6, VEGFA, and TP53) play a critical role in the treatment of CKD by SOLI. The GO analysis and KEGG enrichment analysis indicated that SOLI acts through multiple pathways, including the PI3K/AKT signaling pathway against CKD. Molecular docking showed that the main compounds of SOLI and five key genes had strong binding affinity. In a rat model of adriamycin-induced nephropathy, SOLI significantly ameliorated disease symptoms and improved renal histopathology. Mechanistic studies showed that SOLI upregulated the expression level of Nephrin, inhibited the PI3K/AKT pathway in renal tissues, and ultimately suppressed the activation of autophagy-related proteins in CKD. CONCLUSION: SOLI exerted a renoprotective effect by regulating the Nephrin-PI3K/AKT autophagy signaling pathway, and these findings provide new ideas for the development of SOLI-based therapeutic approaches for CKD.

Does inflammatory bowel disease promote kidney diseases: a mendelian randomization study with populations of European ancestry.

BACKGROUND: This study aimed to investigate a causal relationship between IBD and multiple kidney diseases using two-sample Mendelian randomization (MR) analyses. METHODS: We selected a group of single nucleotide polymorphisms (SNPs) specific to IBD as instrumental variables from a published genome-wide association study (GWAS) with 86,640 individuals of European ancestry. Summary statistics for multiple kidney diseases were obtained from the publicly available GWAS. Genetic data from one GWAS involving 210 extensive T-cell traits was used to estimate the mediating effect on specific kidney disease. Inverse-variance weighted method were used to evaluate the MR estimates for primary analysis. RESULTS: Genetic predisposition to IBD was associated with higher risk of IgA nephropathy (IgAN) (OR, 1.78; 95% CI, 1.45-2.19), but not membranous nephropathy, diabetic nephropathy, glomerulonephritis, nephrotic syndrome, chronic kidney disease, and urolithiasis. CD4 expression on CD4 + T cell had a significant genetic association with the risk of IgAN (OR, 2.72; 95% CI, 1.10-6.72). Additionally, consistent results were also observed when IBD was subclassified as ulcerative colitis (OR, 1.38; 95% CI, 1.10-1.71) and Crohn's disease (OR, 1.37; 95% CI, 1.12-1.68). MR-PRESSO and the MR-Egger intercept did not identify pleiotropic SNPs. CONCLUSIONS: This study provides genetic evidence supporting a positive casual association between IBD, including its subclassification as ulcerative colitis and Crohn's disease, and the risk of IgAN. However, no casual association was found between IBD and other types of kidney diseases. Further exploration of IBD interventions as potential preventive measures for IgAN is warranted.

Dual-functional effect encompassing adsorption and catalysis by Mn-modified iron-based sorbents for arsenic removal: Experimental and DFT study.

Arsenic oxidation plays a crucial role in its removal, which has been identified in numerous studies. However, the mechanisms, especially reaction pathways of arsenic oxidation on sorbent surfaces remain inadequately explored. In this work, the effects of Mn doping on arsenic adsorption and oxidation were first verified by adsorption experiments. Subsequently, DFT calculations were carried out to identify alterations in the adsorption energies, active sites, and oxidation pathways. By integrating the experimental and simulation results, a dual-functional framework encompassing adsorption and catalysis of Mn-modified Fe-based material was distinctly established. For adsorption, the introduction of manganese into iron-based sorbent considerably enhanced As2O3 adsorption owing to the increased active sites available for As2O3 chemisorption and the promotion of surface nucleophilicity. Concerning oxidative catalysis, the incorporation of MnO2 augmented surface catalytic oxidation and provided a substantial amount of active Oload. Consequently, the arsenic oxidation occurring on the Mn-modified sorbent surfaces possessed a lower oxidation RDS energy barrier and a shorter oxidation pathway than those on the bare sorbent surfaces. These experimental and simulation results provide a theoretical basis for the design and application of efficient gaseous arsenic adsorbents.

Causal links between socioeconomic status, leisure sedentary behaviours and gastro-oesophageal reflux disease: a multivariable two-sample Mendelian randomisation study.

INTRODUCTION: We implemented a two-sample multivariable Mendelian randomisation (MR) analyses to estimate the causal effect of socioeconomic status and leisure sedentary behaviours on gastro-oesophageal reflux disease (GERD). METHODS: Independent single-nucleotide polymorphisms associated with socioeconomic status and leisure sedentary behaviours at the genome-wide significance level from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) UK Biobank were selected as instrumental variables. Summary-level data for GERD were obtained from a recent publicly available genome-wide association involving 78 707 GERD cases and 288 734 controls of European descent. Univariable and multivariable two-sample MR analyses, using inverse variance weighted method for primary analyses, were performed to jointly evaluate the effect of socioeconomic status and leisure sedentary behaviours on GERD risk. RESULTS: Three socioeconomic status, including educational attainment (OR 0.46; 95% CI 0.30 to 0.69; p<0.001), average total household income before tax (OR 0.65; 95% CI 0.47 to 0.90; p=0.009) and Townsend Deprivation Index at recruitment (OR 1.60; 95% CI 1.06 to 2.41; p=0.026), were independently and predominately responsible for the genetic causal effect on GERD. In addition, one leisure sedentary behaviour, such as time spent watching television, was independently and predominately responsible for genetic causal effect on GERD (OR 3.74; 95% CI 2.89 to 4.84; p<0.001). No causal effects of social activities and driving on GERD were observed. CONCLUSIONS: Genetically predicted Townsend Deprivation Index at recruitment and leisure watching television were causally associated with increased risk of GERD, and age at completion of full-time education and average total household income before tax were causally associated with decreased risk of GERD.

Effects of Post-Weld Heat Treatment on Microstructure and Mechanical Properties of the Brazed Joint of a Novel Fourth-Generation Nickel-Based Single Crystal Superalloy.

A novel fourth-generation nickel-based single crystal superalloy was brazed with Co-based filler alloy. The effects of post-weld heat treatment (PWHT) on the microstructure and mechanical properties of brazed joints were investigated. The experimental and CALPHAD simulation results show that the non-isothermal solidification zone was composed of M3B2, MB-type boride and MC carbide, and the isothermal solidification zone was composed of γ and γ' phases. After the PWHT, the distribution of borides and the morphology of the γ' phase were changed. The change of the γ' phase was mainly attributed to the effect of borides on the diffusion behavior of Al and Ta atoms. In the process of PWHT, stress concentration leads to the nucleation and growth of grains during recrystallization, thus forming high angle grain boundaries in the joint. The microhardness was slightly increased compared to the joint before PWHT. The relationship between microstructure and microhardness during the PWHT of the joint was discussed. In addition, the tensile strength and stress fracture life of the joints were significantly increased after the PWHT. The reasons for the improved mechanical properties of the joints were analyzed and the fracture mechanism of the joints was elucidated. These research results can provide important guidance for the brazing work of fourth-generation nickel-based single crystal superalloy.

Large-Area Nonfullerene Organic Photovoltaic Modules with a High Certified Power Conversion Efficiency.

Achieving large-area organic photovoltaic (OPV) modules with reasonable cost and performance is an important step toward commercialization. In this work, solution-processed conventional and inverted OPV modules with an area of 216 cm2 were fabricated by the blade coating method. Film uniformity was controlled by adjusting the fabrication parameters of the blade coating procedure. The influence of the concentration of the solutions of the interfacial materials on OPV module performance was investigated. For OPV modules based on the PM6:Y6 photoactive layer, a certificated power conversion efficiency (PCE) of 9.10% was achieved for the conventional OPV modules based on the TASiW-12 interfacial layer while a certificated PCE of 11.27% was achieved for the inverted OPV modules based on the polyethylenimine (PEI) interfacial layer. As for OPV modules based on a commercially available photoactive layer, PV-X Plus, a PCE of 8.52% was achieved in the inverted OPV modules. A halogen-free solvent, o-xylene, was used as the solvent for PV-X Plus, which makes the industrial production much more environmentally friendly.

Controlling waste by waste: a modified landfill leachate coagulation sludge activated peroxymonosulfate process achieves complete BPA degradation.

In this study, a modified coagulation sludge (MCS) from a real landfill leachate coagulation pretreatment was first prepared with polymerized ferric sulfate (PFS) as the activator for PMS to degrade bisphenol A (BPA). The results showed that 43.34% of BPA was adsorbed by MCS when [BPA]0 = 20 mg/L, [MCS]0 = 0.8 g/L, and time = 80 min. Thereafter, by adding 3000 mg/L PMS to initiate the oxidation process, complete BPA removal, i.e. 100%, was achieved in 60 min. In addition, in tap water and municipal wastewater scenarios, 100% and 90.07% removal of BPA were obtained, respectively, and MCS exhibited outstanding performance after repeated use. MCS displayed an excellent adsorption capacity in which chemical adsorption was the main effect, and hydroxyl radicals were the major contributor to BPA degradation. Characterizations of fresh and reacted MCS were conducted, and the results showed that the MCS structure was stable after repeated use, and the surface functional groups, surface defect sites, and iron oxides participated in PMS activation. Overall, this study demonstrated successful recycling of coagulation sludge from landfill leachate pretreatment to activate PMS for environmental pollution control, which is in accordance with the goal of using waste to control waste.

Honokiol inhibits interleukin-induced angiogenesis in the NSCLC microenvironment through the NF-κB signaling pathway.

Tumor angiogenesis, which may be affected by microenvironmental inflammation and promotes tumor development and metastasis, is one of the key reasons contributing to increased mortality. The goal of this study is to investigate how lignin analogs, specifically honokiol (HNK), block angiogenesis induced by the inflammatory milieu of lung cancer. The human lung cancer cell lines A549 and H460 were treated with HNK. Interleukin-1 was employed to mimic an inflammatory tumor microenvironment. Findings demonstrated that HNK drastically decreased the cell viability of A549 and H460 cells. In A549 and H460 cells, HNK also reduced the production of vascular endothelial growth factor (VEGF), the most important marker of tumor angiogenesis. Signal pathway studies revealed that HNK blocked the NF-κB signaling pathway. This effect, in turn, prevented the expression of VEGF by inhibiting the NF-κB signaling pathway. Human umbilical vein endothelial cells (HUVECs) from A549-conditioned medium cultures were subjected to HNK treatment, which decreased tubulogenesis, horizontal and vertical migration, and cell proliferation in HUVECs. Overall, HNK inhibited the NF-κB pathway. This effect resulted in the downregulation of VEGF, thus reducing the viability and angiogenesis of human lung cancer cell lines. In A549 cell xenografts, HNK decreased VEGF expression, tumor angiogenesis, and tumor development. Our research shows that HNK is a potential antiangiogenic molecule for the treatment of lung cancer.

Molecular etiology study of hearing loss in 13 Chinese Han families.

Hearing loss affecting about 2/1000 newborns is the most common congenital disease. Genetic defects caused approximately 70% of patients who have non-syndromic hearing loss. We recruited 13 Chinese Han deafness families who tested negative for GJB2, SLC26A4, and mitochondrial 12S rRNA. The probands of each family were performed whole-exome sequencing (WES) or targeted next-generation sequencing (NGS) for known deafness genes to study for pathogenic causes. We found four novel mutations of CDH23, one novel mutation of MYO15A, one novel mutation of TMC1, one novel mutation of PAX3, and one novel mutation of ADGRV1, one novel CNV of ADGRV1, and one novel CNV of STRC. Hearing loss is a highly hereditary and heterogeneous disease. The results in the limited samples of this study show that Usher and Waardenburg syndrome-related genes account for a major proportion are strongly associated with Chinese Han hearing loss patients negative for GJB2, SLC26A4, and mitochondrial 12S rRNA, followed by STRC resulting in mild to moderate deafness.

YTHDF1 Protects Auditory Hair Cells from Cisplatin-Induced Damage by Activating Autophagy via the Promotion of ATG14 Translation.

N6-methyladenosine (m6A) has been recognized as a common type of post-transcriptional epigenetic modification. m6A modification and YTHDF1, one of its reader proteins, have been documented to play a pivotal role in numerous human diseases via regulating mRNA splicing, translation, stability, and subcellular localization. The chemotherapeutic drug cisplatin (CDP) can damage sensory hair cells (HCs) and result in permanent sensorineural hearing loss. However, whether YTHDF1-mediated modification of mRNA is potentially involved in CDP-induced injury in sensory hair cells was not fully clarified. This study investigated the potential mechanisms for the modification of YTHDF1 in CDP-induced damage in HCs. Here, we discovered that YTHDF1's expression level statistically increased significantly after treating with CDP. Apoptosis and cell death of HCs induced by CDP were exacerbated after the knockdown of YTHDF1, while overexpression of YTHDF1 in HCs alleviated their injury induced by CDP. Moreover, YTHDF1 expression correlated with cisplatin-induced autophagy with statistical significance in HCs; namely, YTHDF1's overexpression enhanced the activation of autophagy, while its deficiency suppressed autophagy and, at the same time, increased the loss of HCs after CDP damage. WB analysis and qRT-PCR results of autophagy-related genes indicated that YTHDF1 promoted the translation of autophagy-related genes ATG14, thus boosting autophagy. Therefore, CDP-induced YTHDF1 expression protected HCs against CDP-induced apoptosis by upregulating the translation of autophagy-related genes ATG14, along with enhancing autophagy. Based on these findings, it can be inferred that YTHDF1 is potentially a target for ameliorating drug-induced HCs damage through m6A modification.

Sources of independent mu components reveal different brain areas involved in motor imagery, motor execution, and movement observation.

To answer the question of whether the same brain circuit(s) facilitates motor imagery (MI), motor execution (ME), and movement observation (MO), we conducted electroencephalography (EEG) experiment combining the three motor conditions in the same experimental runs. The EEG data were analyzed using two different independent component analysis (ICA) decomposition approaches: a single ICA decomposition on all EEG data combined and separate ICA decomposition on the EEG data obtained from the separate conditions. The results indicated that the separate ICA approach may provide a better fit to the EEG data obtained from the separate conditions to deliver specific independent right mu components with distinct topographies for each of the motor conditions. The topography of the MI condition covered the brain regions posterior to the central sulcus (P4 EEG channel); the ME condition covered the brain regions anterior to the central sulcus (C4 EEG channel), and the MO condition had broader coverage with the main activation in the premotor region (CP4 EEG channel). The source localization results also exhibited significant differences among the motor conditions. In addition, the result of single ICA decomposition resembled the result of separate ICA decomposition on the EEG data of ME with similar topographies and closely located EEG sources. This finding may further indicate that the result of single ICA decomposition may be dominated by the ME motor condition because it manifests higher data variance than the other two motor conditions.

Auditory neuropathy: from etiology to management.

PURPOSE OF REVIEW: Auditory neuropathy is a disorder of auditory dysfunction characterized by the normal function of the outer hair cells and malfunction of the inner hair cells, synapses, postsynapses and/or auditory afferent nervous system. This review summarizes the process of discovery and naming of auditory neuropathy and describes the acquired, associated genetic disorders and management available. RECENT FINDINGS: In the last 40 years, auditory neuropathy has undergone a process of discovery, naming and progressive elucidation of its complex pathological mechanisms. Recent studies have revealed numerous acquired and inherited causative factors associated with auditory neuropathy. Studies have analyzed the pathogenic mechanisms of various genes and the outcomes of cochlear implantation. New therapeutic approaches, such as stem cell therapy and gene therapy are the future trends in the treatment of auditory neuropathy. SUMMARY: A comprehensive understanding of the pathogenic mechanisms is crucial in illustrating auditory neuropathy and assist in developing future management strategies.

Failure Of Hearing Acquisition in Mice With Reduced Expression of Connexin 26 Correlates With the Abnormal Phasing of Apoptosis Relative to Autophagy and Defective ATP-Dependent Ca2+ Signaling in Kölliker's Organ.

Mutations in the GJB2 gene that encodes connexin 26 (Cx26) are the predominant cause of prelingual hereditary deafness, and the most frequently encountered variants cause complete loss of protein function. To investigate how Cx26 deficiency induces deafness, we examined the levels of apoptosis and autophagy in Gjb2 loxP/loxP; ROSA26 CreER mice injected with tamoxifen on the day of birth. After weaning, these mice exhibited severe hearing impairment and reduced Cx26 expression in the cochlear duct. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells were observed in apical, middle, and basal turns of Kölliker's organ at postnatal (P) day 1 (P1), associated with increased expression levels of cleaved caspase 3, but decreased levels of autophagy-related proteins LC3-II, P62, and Beclin1. In Kölliker's organ cells with decreased Cx26 expression, we also found significantly reduced levels of intracellular ATP and hampered Ca2+ responses evoked by extracellular ATP application. These results offer novel insight into the mechanisms that prevent hearing acquisition in mouse models of non-syndromic hearing impairment due to Cx26 loss of function.

Overexpression of c-Jun inhibits erastin-induced ferroptosis in Schwann cells and promotes repair of facial nerve function.

Myelin undergoes various changes after nerve injury, and c-Jun has a close relationship with Schwann cells (SCs). However, it remains unclear whether c-Jun can be involved in nerve repair by regulating ferroptosis. To explore this, we first set up a facial nerve injury model and detected the changes of ferroptosis-related proteins and c-Jun by immunofluorescence and Western blot. Then, we cultured RSC 96 and pSCs, and studied the potential regulatory relationships by a combination of experimental methods such as CCK-8, ELISA, immunofluorescence, qRT-PCR, Western blot and viral transfection. Finally, we corroborated the role of c-Jun through animal experiments. Our experiments revealed that ferroptosis occurs after facial nerve injury. Erastin decreased GPX4, c-Jun proteins and GSH content, while PTGS2, NRF2, HO-1 proteins, MDA, Fe2+ and ROS contents increased. This effect was inhibited after c-Jun overexpression but was reversed after the addition of c-Jun siRNA. Besides, we proved in vivo that c-Jun could inhibit ferroptosis and promote the recovery of facial nerve function. In conclusion, our study identified the relationship between c-Jun and ferroptosis during peripheral nerve injury repair, which provides new ideas for studying peripheral nerve injury and repair.

Degradation of refractory organic matter in the effluent from a semi-aerobic aged refuse biofilter-treated landfill leachate by a nano-Fe3O4 enhanced ozonation process.

In this study, the transformation and degradation mechanisms of refractory organic matter in biologically treated leachate from a semi-aerobic aged refuse biofilter (SAARB) in a nano-Fe3O4 enhanced ozonation process (nFe3O4-O3) were investigated in batch experiments. A continuous experiment then confirmed the effectiveness of the process for SAARB effluent treatment. In a batch experiment, the effects of influencing factors, including nFe3O4 dosage, O3 dosage and initial pH on the treatment performance of nFe3O4-O3 process, were comprehensively investigated. The results showed that when the nFe3O4 dosage = 6 g L-1, O3 dosage = 0.15 L minute-1 and initial pH = 7, the total organic carbon, absorbance at 254 nm and colour number removal efficiencies were 40.58%, 62.55% and 89.80%, respectively. In addition, most of the humic- and fulvic-like substances in the SAARB effluent were removed, and the condensation degree, aromaticity and humification degree of the organics were substantially reduced. The morphology and elemental valence state analysis showed that the nFe3O4 in the process was relatively stable and could form an nFe3O4-organic complex. Therefore, the probability of organics reacting with hydroxyl radical increased and the oxidation efficiency was enhanced. In the continuous experiment, both the O3 dosage and hydraulic retention time (HRT) were the key influencing factors. The treatment efficiency of the nFe3O4-O3 process was enhanced at a higher O3 dosage and longer HRT. The electrical energy consumption of the continuous nFe3O3-O3 process was calculated to be 17.72 kW h m-3 in SAARB effluent treatment. This study proved the feasibility of biologically treated landfill leachate treatment by the nFe3O3-O3 process.

Hearing Protection Outcomes of Analog Electrode Arrays Coated with Different Drug-Eluting Polymer Films Implanted into Guinea Pig Cochleae.

OBJECTIVE: To investigate the hearing protection outcomes of different drug-eluting analog electrode arrays implanted into guinea pig cochleae. METHODS: Sixty guinea pigs were randomly divided into a negative control group and five experimental groups implanted separately with blank (drug carrier), dexamethasone (DXM), aracytine (Ara-C), Ara-C+DXM, and nicotinamide adenine dinucleotide (NAD+) eluting analog electrode arrays. Micro CT was used to supervise the surgical procedure. Auditory brainstem response (ABR) thresholds of the guinea pigs were measured and analyzed. RESULTS AND CONCLUSIONS: Compared with the negative control, all other groups showed a significant increase in ABR threshold (p<0.001) after surgery. Among them, there was no obvious difference between the blank (0 vs 90 days: 59.70±10.57 vs 64.60±9.47 dB SPL) and the NAD+ group (0 vs 90 days: 59.90±9.87 vs 64.70±8.65 dB SPL). On the other hand, the ABR thresholds in the DXM (0 days: 58.10±10.73 dB SPL; 90 days: 51.70±9.07 dB SPL) and the Ara-C group (0 days: 59.00±10.05 dB SPL; 90 days: 51.60±8.48 dB SPL) decreased significantly compared with the former two groups (p<0.001). However, the Ara-C+DXM group showed no further benefit (p>0.05). In addition, a significantly higher survival rate of spiral ganglion neurons in cochleae was observed in the Ara-C and/or DXM groups.

Separation of normal and impaired dynamic cerebral autoregulation using deep embedded clustering: a proof-of-concept study.

Objective. A previous study has shown that a data-driven approach can significantly improve the discriminative power of transfer function analysis (TFA) used to differentiate between normal and impaired cerebral autoregulation (CA) in two groups of data. The data was collected from both healthy subjects (assumed to have normal CA) and symptomatic patients with severe stenosis (assumed to have impaired CA). However, the sample size of the labeled data was relatively small, owing to the difficulty in data collection. Therefore, in this proof-of-concept study, we investigate the feasibility of using an unsupervised learning model to differentiate between normal and impaired CA on TFA variables without requiring labeled data for learning.Approach. Continuous arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), which were recorded simultaneously for approximately 10 min, were included from 148 subjects (41 healthy subjects, 31 with mild stenosis, 13 with moderate stenosis, 22 asymptomatic patients with severe stenosis, and 41 symptomatic patients with severe stenosis). Tiecks' model was used to generate surrogate data with normal and impaired CA. A recently proposed unsupervised learning model was optimized and applied to separate the normal and impaired CA for both the surrogate data and real data.Main results. It achieved 98.9% and 74.1% accuracy for the surrogate and real data, respectively.Significance. To our knowledge, this is the first attempt to employ an unsupervised data-driven approach to assess CA using TFA. This method enables the development of a classifier to determine the status of CA, which is currently lacking.

Sub-lethal toxicity and elimination of the cocaine metabolite, benzoylecgonine: a narrative review.

Cocaine abuse is a serious global public health and social problem, and cocaine detoxification remains a challenge. Benzoylecgonine (BE) is the main toxic metabolite after cocaine consumption, with a longer retention time in the body and environment than cocaine itself. According to many studies, the toxicity of BE to humans is as significant as cocaine itself. Moreover, BE is recognized as an addictive drug contaminant in the environment, especially the freshwater system, leading to worries of its ecotoxicity. Extensive studies on the adverse effects of BE on both humans and ecology have been conducted, showing a marked sub-lethal toxicity of BE to diverse organisms. To eliminate BE in vivo and in vitro, various elimination methods have been developed and their BE removal capacity were evaluated. In this review, we aimed to summarize information in the literature to understand better BE toxicity and elimination that may facilitate the clinical treatment of cocaine abuse. By studying the critical role of BE in cocaine abuse, we propose that the ideal treatment for cocaine abuse should not only detoxify cocaine itself but also remove or degrade BE. Emphasizing the necessity of developing effective BE elimination methods is significant for the development of potential clinical treatments and environmental protections.

Expanding the coronary tree reconstruction to smaller arteries improves the accuracy of FFRCT.

OBJECTIVES: We attempted to improve the accuracy of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (FFRCT) by expanding the coronary tree in the computational fluid dynamics (CFD) domain. An observational study was performed to evaluate the effects of extending the coronary tree analysis for FFRCT from a minimal diameter of 1.2 to 0.8 mm. METHODS: Patients who underwent CCTA and interventional FFR were enrolled retrospectively. Seventy-six patients qualified based on the inclusion criteria. The three-dimensional (3D) coronary artery tree was reconstructed to generate a finite element mesh for each subject with different lower limits of luminal diameter (1.2 mm and 0.8 mm). Outlet boundary conditions were defined according to Murray's law. The Newton-Krylov-Schwarz (NKS) method was applied to solve the governing equations of CFD to derive FFRCT. RESULTS: At the individual patient level, extending the minimal diameter of the coronary tree from 1.2 to 0.8 mm improved the sensitivity of FFRCT by 16.7% (p = 0.022). This led to the conversion of four false-negative cases into true-positive cases. The AUC value of the ROC curve increased from 0.74 to 0.83. Moreover, the NKS method can solve the computational problem of extending the coronary tree to an 0.8-mm luminal diameter in 10.5 min with 2160 processor cores. CONCLUSIONS: Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. The NKS method can achieve favorable computational times for future clinical applications. KEY POINTS: • Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. • The NKS method applied in our study can effectively reduce the computational time of this process for future clinical applications.