First-in-Human Evaluation of [18F]FDOPA Produced by Organo-Photoredox Reactions.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [18F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [18F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

Nicotinamide riboside ameliorates survival time and motor dysfunction in an MPTP-Induced Parkinson's disease zebrafish model through effects on glucose metabolism and endoplasmic reticulum stress.

Nicotinamide riboside (NR) is a precursor and exogenous supplement of nicotinamide adenine dinucleotide (NAD+). NR has been shown to play a beneficial role in a variety of neurodegenerative diseases. A phase 1 clinical trial identified NR as a potential neuroprotective therapy for Parkinson's disease (PD). However, the mechanism of action of NR in PD has not been fully elucidated. Therefore, the present study aimed to investigate the potential effects of NR on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish and its underlying mechanisms. The results showed that NR improved motor dysfunction, survival time, dopamine neurons, and peripheral neurons, as well as the NAD+ levels in the MPTP-affected PD zebrafish model. In addition, transcriptome sequencing analysis revealed that, after NR treatment, differentially expressed genes were significantly enriched in the glucose metabolism and protein processing pathways in the endoplasmic reticulum (ER). Quantitative PCR (qPCR) revealed that the mRNA levels of the glycoheterotrophic enzyme (involved in glucose metabolism) were significantly decreased, and the glycolytic enzyme mRNA expression levels were significantly increased. The results of the non-targeted metabolomic analysis showed that NR treatment significantly increased the levels of metabolites such as nicotinic acid ,nicotinamide, d-glucose (from the gluconeogenesis and glycolysis metabolism pathways) and some glucogenic amino acids, such as glutamine. Importantly, NR ameliorated MPTP-induced endoplasmic reticulum stress (ERS) in the PD zebrafish model through the Perk-Eif2α-Atf4-Chop pathway. These results highlight the neuroprotective effect of NR in the present PD zebrafish model through modulation of glucose metabolism and ERS via the Perk-Eif2α-Atf4-Chop pathway and provide valuable mechanistic insights into the treatment of PD.

Bridging techniques compared with direct endovascular therapy for stroke due to tandem occlusion: A systematic review and meta-analysis.

The superiority of the bridging strategy of intravenous thrombolysis (IVT) plus endovascular therapy (EVT) to EVT alone for the anterior circulation with tandem vascular occlusion (TO) has not been specifically addressed by a single randomized trial. Analysis of 15 studies (n = 1857 patients) revealed that 90 Day good functional outcomes (MRS≤2) were better for bridging therapy (IVT + EVT) than for dEVT (OR:1.39, 95%CI: 1.09-1.79, p = 0.008); 90-day mortality was lower for IVT + EVT than for dEVT (OR: 0.57; 95%CI: 0.40-0.81, p = 0.002) and rates of successful recanalization were higher for IVT + EVT than for dEVT (OR: 1.79, 95%CI: 1.36-2.36, p<0.0001). However, there was no significant difference in the incidence of symptomatic. intracranial hemorrhage (sICH) between groups (OR 0.91, 95%CI 0.64-1.31, p = 0.62).In conclusion, Patients receiving IVT + EVT have a better functional outcome, lower death rate and a higher rate of successful recanalization than those receiving dEVT but there was no difference in sICH risk between the two treatments.

Association of tirofiban treatment with outcomes following endovascular therapy in cardioembolic stroke: insights from the RESCUE BT randomized trial.

BACKGROUND AND PURPOSE: The efficacy and safety of tirofiban in endovascular therapy for cardioembolic ischemic stroke patients remain controversial. This study aimed to evaluate the role of intravenous tirofiban before endovascular therapy in cardioembolic stroke. METHODS: This post hoc analysis utilized data from the RESCUE BT (Endovascular Treatment With versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke) trial, which was an investigator-initiated, randomized, double-blind, placebo-controlled trial. Participants were randomized to receive either tirofiban or a placebo in a 1:1 ratio before undergoing endovascular therapy. The study included patients aged 18 years or older, presenting with occlusion of the internal carotid artery or middle cerebral artery (MCA) M1/M2 within 24 h of the last known well time, and with a stroke etiology of cardioembolism. The primary efficacy outcome was global disability at 90 days, assessed using the modified Rankin Scale (mRS). The safety outcome included symptomatic intracranial hemorrhage (sICH) within 48 h and mortality within 90 days. RESULTS: A total of 406 cardioembolic stroke patients were included in this study, with 212 assigned to the tirofiban group and 194 assigned to the placebo group. Tirofiban treatment did not correlate with a favorable shift towards a lower 90-day mRS score (adjusted common odds ratio [OR], 0.91; 95% CI 0.64-1.3; p = 0.617). However, the tirofiban group had a significantly higher risk of symptomatic intracranial hemorrhage (sICH) within 48 h (adjusted OR, 3.26; 95% CI 1.4-7.57; p = 0.006) compared to the placebo group. The adjusted odds ratio (aOR) for mortality within 90 days was 1.48 (95% CI 0.88-2.52; p = 0.143). CONCLUSIONS: Tirofiban treatment was not associated with a lower level of disability and increased the incidence of sICH after endovascular therapy in cardioembolic stroke patients.

The relationship between the number of stenotic coronary arteries and the gut microbiome in coronary heart disease patients.

An increasing number of studies have shown that the gut microbiome plays an important role in the development of coronary heart disease (CHD). However, there are no clear studies on the relationship between the gut microbiome and the number of stenotic coronary arteries. To clarify whether the gut microbiome is associated with the number of stenotic coronary arteries in CHD, we performed the 16S rRNA gene sequencing for the V3-V4 region in the gut microbiota from 9 healthy controls (C) and 36 CHD patients, which including 25 CHD patients with multivessel (MV) lesion and 11 CHD patients with single-vessel (SV) lesion. It showed that the abundance of the genus Escherichia-Shigella was significantly increased in the MV and SV groups compared with C group, while the abundance of the genera Subdoligranulum and Collinsella was significantly decreased. Biomarkers based on three gut microbiotas (Escherichia-Shigella, Subdoligranulum, and Collinsella) and three plasma metabolites(left atrial diameter (LA), low density lipoprotein (LDL), and total bile acids (TBA)) were able to distinguish CHD patients with different numbers of stenotic coronary arteries. Functional prediction of the gut microbiome was performed based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The results showed that the gut microbial function of MV and SV group patients was richer than C group in betaine biosynthesis and unsaturated fatty acid biosynthesis, in the contrast less than C group in sphingolipid metabolism and primary bile acid biosynthesis. In summary, our study showed that the composition and function of the gut microbiome changed significantly from healthy controls to CHD patients with different numbers of coronary lesions.

Alberta Stroke Program Early CT Score applied to hyperdense lesion on noncontrast CT immediately post-thrombectomy is a predictor of poor outcome in acute ischemic stroke: A case-control study.

We aimed to evaluate whether Alberta Stroke Program Early CT Score (ASPECTS) applied to hyperdense lesion on noncontrast CT obtained immediately post-thrombectomy (post-ASPECTS) is useful for predicting poor outcome. We retrospectively reviewed patients who underwent noncontrast CT (NCCT) immediately after mechanical thrombectomy between January 2017 and July 2020 in our comprehensive stroke center. We collected baseline NCCT and post-ASPECTS score. The sensitivity, specificity, and positive and negative predictive values of the post-ASPECTS in predicting clinical outcome were calculated. A total of 223 patients were included. The hyperdense lesion on NCCT immediately after endovascular thrombectomy presented in 85.7% (191/223) patients, poor clinical outcome was in 56.1% (112/191) of hyperdense lesion patients. Low post-ASPECTS was associated with poor outcome (OR 0.390; 95% CI 0.258-0.589; P = .001), with an AUCROC curve of 0.753 (95% CI 0.684-0.822), while baseline NCCT-ASPECTS was not (OR 0. 754; 95% CI 0. 497-1.144; P = .185). A score ≤ 7 in post-ASPECTS was the best cut-off to poor clinical outcome (sensitivity 84.8%; specificity 52.7%; positive predictive value 68.4%; negative predictive value 73.8%). Our results point to the proportion of patients who present hyperdense lesion on NCCT is very high, post-ASPECTS could predict poor clinical outcomes in patients with stroke treated with endovascular mechanical thrombectomy, and post-ASPECTS may achieved better predictive value than baseline ASPECTS.

A novel compound heterozygous mutation of the MTO1 gene associated with complex oxidative phosphorylation deficiency type 10.

BACKGROUND: The mitochondrial tRNA translation optimization 1 (MTO1) gene, which is closely related to defective mitochondrial oxidative phosphorylation, is an evolutionarily conserved protein expressed in high energy-demanding tissues and is associated with complex oxidative phosphorylation deficiency type 10 (COXPD10) in humans. Related cases and studies are still scarce and have not been reported in the Chinese region. MATERIALS AND METHODS: Detailed clinical assessment was applied to the patient. Based on next-generation sequencing technology, we performed whole-exome sequencing of the patient and the parents. Sanger sequencing was used for validation. Bioinformatics software and protein simulations were used to predict the pathogenicity of the variants. RESULTS: The patient was diagnosed with a possible association with mitochondrial disease according to the clinical manifestations and physical examination. A novel frameshift mutation c.344delA (p. Asn115Thrfs*11) and a novel point mutation c.1055C > T (p. Thr352Met) in the MTO1 gene were identified. They were found to cause abnormal changes in amino acids and the protein by biochemical tools, indicating it may be pathogenic. CONCLUSION: We present two novel and possibly pathogenic variants in the MTO1 gene in a Chinese Han family.

miR­541­3p inhibits the viability and migration of vascular smooth muscle cells via targeting STIM1.

The transformation of vascular smooth muscle cells (VSMCs) into the proliferative migratory phenotype in the plaque area contributes to stable plaque formation and facilitates the pathogenesis of atherosclerosis. Stromal interaction molecule 1 (STIM1) has been identified to promote the proliferation of VSMCs, suggesting that STIM1 may be a potent target for the prevention and treatment of atherosclerosis. Bioinformatics analysis has previously predicted STIM1 as a target of microRNA (miR)­541­3p. The present study aimed to determine the effect of the miR­541­3p/STIM1 axis on the progression of atherosclerosis in vitro. Oxidized low­density lipoprotein (ox­LDL)­treated VSMCs were used as an in vitro atherosclerosis model. Cell Counting Kit­8 and Transwell migration assays were used to analyze cell viability and migration, respectively. Reverse transcription­quantitative PCR and western blotting were applied to measure mRNA and protein expression levels, respectively. The association between miR­541­3p and STIM1 was detected using a dual luciferase gene reporter assay. The results of the present study revealed that ox­LDL treatment significantly downregulated miR­541­3p expression levels and upregulated STIM1 expression levels in VSMCs. In addition, ox­LDL stimulation enhanced cell viability and migration. The overexpression of miR­541­3p significantly reversed the ox­LDL­mediated increase in cell viability and migration, whereas the knockdown of miR­541­3p expression enhanced the ox­LDL­mediated effects. STIM1 was confirmed to be a target gene of miR­541­3p in VSMCs. The knockdown of STIM1 significantly impaired the stimulatory effects of miR­541­3p knockdown on cell viability and migration. In conclusion, the findings of the present study suggested that miR­541­3p may efficiently repress VSMC viability and migration by targeting STIM1 under the treatment of ox­LDL. These results indicated that the miR­541­3p/STIM1 axis may represent a potent target to modulate VSMC viability and migration.

SOX21-AS1 modulates neuronal injury of MMP+-treated SH-SY5Y cells via targeting miR-7-5p and inhibiting IRS2.

Parkinson's disease (PD), caused by the decreased number of dopaminergic neurons in the substantia nigra, is identified as the second most familiar age-dependent neurodegenerative disease to the public. Long non-coding RNAs (lncRNAs) have been reported to participate in the development of PD. In our research, the expression of lncRNA SRY-box transcription factor 21 antisense divergent transcript 1 (SOX21-AS1) was up-regulated in 1-methyl-4-phenylpyridinium (MMP+)-treated SH-SY5Y cells. In addition, SOX21-AS1 depletion weakened the cell injury induced by MMP+. Moreover, SOX21-AS1 knockdown decreased Reactive Oxygen Species (ROS) generation and levels of TNF-α, IL-1ß and IL-6, but increased SOD activity. However, SOX21-AS1 up-regulation led to opposite results. Further, SOX21-AS1 could bind with miR-7-5p, whose overexpression relieved MMP+-induced cell injury. Additionally, insulin receptor substrate 2 (IRS2) served as the target gene of miR-7-5p, and its expression was positively modulated by SOX21-AS1. Similarly, IRS2 knockdown also had alleviative effects on cell injury stimulated by MMP+ treatment. In sum up, our study demonstrated a new regulatory network consisted of SOX21-AS1, miR-7-5p and IRS2 in SH-SY5Y cells, supplying with a better comprehension about the pathogenic mechanism of PD.

Association of plasma trimethylamine-N-oxide levels with post-stroke cognitive impairment: a 1-year longitudinal study.

BACKGROUND AND AIMS: Post-stroke cognitive impairment (PSCI) is a clinical condition arising from stroke and causes significant changes to memory, thinking, and behavior. Trimethylamine-N-oxide (TMAO), the metabolite produced by gut microbiota, has mechanistic relevance to atherosclerotic diseases. This study aimed to investigate whether an association existed between elevated plasma TMAO levels and PSCI. METHODS: Consecutive patients with acute ischemic stroke were prospectively enrolled during Jan. 2017 to Dec. 2017. TMAO concentration was measured within 24 h after admission. PSCI was assessed using the Mini-Mental State Examination (MMSE) score after 1 year and defined as MMSE score ≤ 26. Binary logistic regression analysis was used to determine the contribution of TMAO level in the prediction of PSCI. RESULTS: Of the 256 patients studied (age, 67.1 ± 11.0 years; male, 54.3%), 86 (33.6%) patients were diagnosed as PSCI. The mean TMAO level was 5.6 ± 2.4 µM, with quartile level as follows: < 3.9 µM (first quartile), 3.9-5.1 µM (second quartile), 5.2-7.4 µM (third quartile), and > 7.4 µM (fourth quartile). After controlling for potential confounders, multivariable logistic analysis showed that higher level of plasma TMAO was an independent predictor for cognitive impairment in post-stroke patients (the quartile 1 was used as reference, the quartile 4 odds ratio, 3.304; 95% confidence intervals, 1.335-8.178; P = 0.010). CONCLUSIONS: This study demonstrated that increasing plasma level of TMAO may be associated with PSCI.

A network-based analysis for mining the risk pathways in glioblastoma.

The most malignant type of brain tumour is glioblastoma multiforme (GBM). Patients with GBM often have a poor prognosis, as a result of incomplete or inaccurate diagnoses. Regulatory pathways have been demonstrated to serve important roles in complex human diseases. Therefore, deciphering these risk pathways may shed light on the molecular mechanisms underlying GBM progression. In the present study, differentially expressed genes and microRNAs (miRNAs) in a publicly available database were identified between normal and tumour samples. To determine the pathophysiology and molecular mechanisms underlying GBM, integrated network analysis was performed to mine GBM-specific risk pathways. Specifically, a GBM-specific regulatory network was constructed that integrated manually curated GBM-associated transcription and post-transcriptional data resources, including transcription factors and miRNAs. A total of 1,827 differentially expressed genes and 30 miRNAs were identified. The differentially expressed genes were significantly enriched in a number of immune response-associated functions. Based on the GBM-specific regulatory network, 15 risk regulatory pathways containing not only known regulators, but also potential novel targets that might be involved in tumourigenesis were identified. Network analysis provides a strategy for leveraging genomic data to identify potential oncogenic pathways and molecular targets for GBM.

Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.

BACKGROUND: This study aimed to investigate the cerebral blood flow (CBF) and frontal lobe cognitive function in severe internal carotid artery (ICA) stenosis patients with different types of collateral circulation. METHODS: One hundred twenty-six patients with severe unilateral ICA stenosis were enrolled. Digital subtraction angiography (DSA) was performed to recruit patients with one of three common types of collateral circulation: anterior communicating artery (AcoA), posterior communicating artery (PcoA) and ophthalmic artery (OA). The hemodynamic parameters of the middle cerebral artery (MCA) were measured using transcranial Doppler (TCD), and the individual frontal lobe cognitive attention functions were evaluated using Word Fluency Test, Trail-Making Test (TMT), Digit Span, and Stroop Color Word Test (SCWT). The correlation between hemodynamic changes and the scores of all tasks was analyzed. RESULTS: On the side of arterial stenosis, the CBF velocities were highest in AcoA group and lowest in the OA group. All patients performed worse in TMT and Digit Span than the matched normal controls. The AcoA group exhibited a lower pulsatility index (PI) and a longer response time in the Stroop task, but had a higher accuracy rate in the Stroop task and higher scores in Word Fluency Test than the PcoA and OA groups. In all the three groups, PI was positively correlated with the accuracy rate for Stroop interference effects. CONCLUSIONS: Our findings suggested that the frontal lobe cognitive function of patients with ICA was impaired, and AcoA collaterals may be beneficial for selective attention functions, whereas OA collaterals may be associated with impairment of selective attention functions. Additionally, a high PI may be an indicator for identifying impaired selective attention in patients with severe ICA stenosis.

Sensor placement optimization in the artificial lateral line using optimal weight analysis combining feature distance and variance evaluation.

Artificial lateral line is a multi-sensor system, mimicking the lateral line of fish to perceive the parameters of flow field. However, it can easily lead to information loss or redundancy with limited number of sensors due to unsuitable sensor placement. An optimal weight analysis algorithm is proposed to solve the problem on sensor placement of robotic fish. Firstly, signal features are extracted from the pressure data, which are collected from candidate sensor locations in different conditions. Then the improved distance evaluation is used to assess each feature, and the feature distance factor is regarded as the weight for distinguishing. Combined with the analysis of variance, the contribution vector of sensor locations is obtained. Three indexes selected by the algorithm are introduced to compare the sensor subsets. The results in both simulation and experiment show the effectiveness of the algorithm. The optimal number of sensors on the robotic fish is also studied.

Increased Expression of Apo-J and Omi/HtrA2 After Intracerebral Hemorrhage in Rats.

OBJECTIVE: To investigate the changes of Apo-J and Omi/HtrA2 protein expression in rats with intracerebral hemorrhage. METHODS: 150 Sprague-Dawley adult rats were randomly divided into 3 groups: (1) normal control (NC) group, (2) sham group, and (3) intracerebral hemorrhage (ICH) group. The data were collected at 6 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, and 7 days. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling staining. The distributions of the Apo-J and Omi/HtrA2 proteins were determined by immunohistochemical staining. The levels of Apo-J mRNA and Omi/HtrA2 mRNA expressions were examined by real-time polymerase chain reaction. RESULTS: Apoptosis in the ICH group was higher than in the sham and NC groups (P < 0.05). Both the Apo-J and Omi/HtrA2 expression levels were increased in the peripheral region of hemorrhage, with a peak at 3 days. The Apo-J mRNA level positively correlated with the HtrA2 mRNA level in the ICH group (r = 0.883, P < 0.001). CONCLUSION: The expressions of Apo-J and Omi/HtrA2 increased in parallel in the peripheral region of rat cerebral hemorrhage. Local high expression of Apo-J in the peripheral regions may play a neuroprotective role by inhibiting apoptosis via the Omi/HtrA2 pathway after hemorrhage.

The association between COMT Val158Met gene polymorphism and antipsychotic-induced tardive dyskinesia risk.

PURPOSE: Catechol-O-methyltransferase (COMT) Val158Met gene polymorphism has been implicated the association with Tardive dyskinesia (TD) risk. However, lots of studies have reported contradictory results, so we conducted a meta-analysis to investigate the association between the COMT Val158Met gene polymorphism and TD susceptibility. MATERIALS AND METHODS: The PubMed, Embase, China National Knowledge Internet and Wanfang Database were researched up to 5 January 2015. The odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the relationship, and the statistical analyses were carried out by STATA 11.0 software. RESULTS: In total, 1206 cases and 1680 controls from 11 case-control studies were included in the present study. The overall and subgroup pooled results indicated no significant association between COMT Val158Met gene polymorphism and TD susceptibility in all gene models (AA + AG vs. GG, OR: 0.98, 95% CI = 0.76-1.26, P = 0.87; AA vs. AG + GG, OR: 1.15, 95% CI = 0.93-1.42, P = 0.271; AA vs. GG, OR: 1.15, 95% CI = 0.90-1.49, P = 0.27; AG vs. GG, OR: 0.95, 95% CI = 0.80-1.14, P = 0.59; A vs. G, OR: 1.05, 95% CI = 0.93-1.17, P = 0.43). CONCLUSION: The study suggested COMT Val158Met gene polymorphism may not be an independent risk factor for TD susceptibility, especially in East Asians.