Levosimendan mediates the BMP/Smad axis through upregulation of circUSP34-targeted miR-1298 to alleviate pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world's population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown. METHODS: We used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model. RESULTS: Our results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype. CONCLUSION: We have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms.

Thickness-independent capacitance of vertically aligned liquid-crystalline MXenes.

The scalable and sustainable manufacture of thick electrode films with high energy and power densities is critical for the large-scale storage of electrochemical energy for application in transportation and stationary electric grids. Two-dimensional nanomaterials have become the predominant choice of electrode material in the pursuit of high energy and power densities owing to their large surface-area-to-volume ratios and lack of solid-state diffusion1,2. However, traditional electrode fabrication methods often lead to restacking of two-dimensional nanomaterials, which limits ion transport in thick films and results in systems in which the electrochemical performance is highly dependent on the thickness of the film1-4. Strategies for facilitating ion transport-such as increasing the interlayer spacing by intercalation5-8 or introducing film porosity by designing nanoarchitectures9,10-result in materials with low volumetric energy storage as well as complex and lengthy ion transport paths that impede performance at high charge-discharge rates. Vertical alignment of two-dimensional flakes enables directional ion transport that can lead to thickness-independent electrochemical performances in thick films11-13. However, so far only limited success11,12 has been reported, and the mitigation of performance losses remains a major challenge when working with films of two-dimensional nanomaterials with thicknesses that are near to or exceed the industrial standard of 100 micrometres. Here we demonstrate electrochemical energy storage that is independent of film thickness for vertically aligned two-dimensional titanium carbide (Ti3C2T x ), a material from the MXene family (two-dimensional carbides and nitrides of transition metals (M), where X stands for carbon or nitrogen). The vertical alignment was achieved by mechanical shearing of a discotic lamellar liquid-crystal phase of Ti3C2T x . The resulting electrode films show excellent performance that is nearly independent of film thickness up to 200 micrometres, which makes them highly attractive for energy storage applications. Furthermore, the self-assembly approach presented here is scalable and can be extended to other systems that involve directional transport, such as catalysis and filtration.

Phage cocktail alleviated type 2 diabetes by reshaping gut microbiota and decreasing proinflammatory cytokines.

Type 2 diabetes (T2D), a global health concern, is closely associated with the gut microbiota. Restoration of a balanced microbiota and intestinal homeostasis benefit therapy of T2D. Some special phages may selectively alter the gut microbiota without causing dysbiosis, such as MS2 and P22. However, scarcely systematic analysis of cascading effects triggered by MS2 and P22 phages on the microbiota, as well as interactions between specific gut bacteria and systemic metabolism, seriously inhibit the development of positive interventions of phages. Based on multi-omic analysis, we analyzed the intrinsic correlations among specific microbiota, their bioactive metabolites, and key indicators of T2D. We found that gavage of the MS2-P22 phage cocktail could significantly alter the gut microbiome to attenuate dysbiosis of diabetic C57BL/6 mice caused by high-fat diets (HFDs) and streptozotocin (STZ), by affecting microbial compositions as well as their metabolic pathways and metabolites, especially increasing amounts of short-chain fatty acid-producing (SCFA-producing) bacteria (e.g., Blautia and Romboutsia) and short-chain fatty acids (SCFAs). Correspondingly, a noteworthy reduction in the number of several opportunistic pathogens occurred, e.g., Candidatus Saccharimonas, Aerococcus, Oscillibacter, Desulfovibrio, and Clostridium sensu stricto 1. Synchronously, the levels of proinflammatory cytokines and lipopolysaccharide (LPS) were reduced to recover gut barrier function in T2D mice. These findings might benefit the development of a new dietary intervention for T2D based on phage cocktails. KEY POINTS: • Intestinal barrier integrity of T2D mice is improved by a phage cocktail • Negative relationship between Muribaculaceae and Corynebacterium reshaped gut microbiota • Acetate, propionate, and butyrate decreased the level of proinflammatory factors.

The value of ictal scalp EEG in focal epilepsies surgery: a retrospective analysis.

OBJECTIVE: To describe the association between preoperative ictal scalp electroencephalogram (EEG) results and surgical outcomes in patients with focal epilepsies. METHODS: The data of consecutive patients with focal epilepsies who received surgical treatments at our center from January 2012 to December 2021 were retrospectively analyzed. RESULTS: Our data showed that 44.2% (322/729) of patients had ictal EEG recorded on video EEG monitoring during preoperative evaluation, of which 60.6% (195/322) had a concordant ictal EEG results. No significant difference of surgery outcomes between patients with and without ictal EEG was discovered. Among MRI-negative patients, those with concordant ictal EEG had a significantly better outcome than those without ictal EEG (75.7% vs. 43.8%, p = 0.024). Further logistic regression analysis showed that concordant ictal EEG was an independent predictor for a favorable outcome (OR = 4.430, 95%CI 1.175-16.694, p = 0.028). Among MRI-positive patients, those with extra-temporal lesions and discordant ictal EEG results had a worse outcome compared to those without an ictal EEG result (44.7% vs. 68.8%, p = 0.005). Further logistic regression analysis showed that discordant ictal EEG was an independent predictor of worse outcome (OR = 0.387, 95%CI 0.186-0.807, p = 0.011) in these patients. Furthermore, our data indicated that the number of seizures was not associated with the concordance rates of the ictal EEG, nor the surgical outcomes. CONCLUSIONS: The value of ictal scalp EEG for epilepsy surgery varies widely among patients. A concordant ictal EEG predicts a good surgical outcome in MRI-negative patients, whereas a discordant ictal EEG predicts a poor postoperative outcome in lesional extratemporal lobe epilepsy.

The Screening of Piwi-Interacting RNA Biomarkers in Sporadic Parkinson's Disease.

Background: piRNAs play key roles in various diseases. However, the role of piRNAs in sporadic Parkinson's disease (PD) remains unclear. This study was conducted to explore key piRNAs that can be used as biomarkers for sporadic Parkinson's disease. Methods: Differentially expressed piRNAs (DEPs) and their interaction were investigated using bioinformatics analysis, while the diagnostic value and expression of the selected piRNAs were detected. Results: 42 DEPs were screened between PD and controls. Moreover, most of the physiological piRNA-piRNA interactions and linkages in normal samples had been altered in the sporadic PD samples. 14 overlapping piRNAs were selected, and six key piRNA biomarkers were screened. The different expressions of piR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, and piR-hsa-2524778 had high efficiency and sensitivity in the diagnosis of PD. Conclusion: PiR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, piR-hsa-758566 and piR-hsa-2524778 could be biomarkers of PD.

A convolutional neural network-based, quantitative complete blood count scattergram-mapping framework promptly screens acute promyelocytic leukemia with high sensitivity.

BACKGROUND: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by its rapidly progressive and fatal clinical course if untreated, although it is curable if treated in a timely manner. Promptly screening patients who have results that are suspicious for APL is vital to overcome early death. METHODS: The authors developed an innovative framework consisting of ResNet-18, a convolutional neural network architecture, with the objective of quantitatively mapping a complete blood count (CBC) scattergram to quickly and robustly indicate a probable susceptibility to APL. Three hundred and twenty scattergrams of the white blood cell differential channel from 51 patients with APL, 510 scattergrams from 105 patients who had non-APL AML, and 320 scattergrams from 320 healthy controls were randomly stratified at a ratio of 4:1 and split into training and testing data sets to accomplish five-fold cross-validation. RESULTS: Both the area under the curve and the average precision of >0.99 were achieved in each fold. Three hundred four of the 320 APL scattergrams (95%) were correctly flagged by the model, which outcompeted the CBC review rules recommended by the International Society of Laboratory Hematology (all p < .001). External validation based on an independent testing data set that included 56 scattergrams from 31 patients with APL, 56 scattergrams from 55 patients with non-APL AML, and 64 scattergrams from 64 healthy controls also confirmed the sensitivity and specificity of the framework. CONCLUSIONS: To the authors' knowledge, their convolutional neural network-based framework is the first to use scattergram output from routine CBC analysis to map suspicious APL early with outstanding sensitivity, specificity, and precision. The authors also describe a new CBC workflow incorporating this framework upstream of the morphologic review, which would provide the earliest flag for APL. PLAIN LANGUAGE SUMMARY: The authors propose an innovative way to visualize complete blood counts (CBCs) by mapping the difference in white blood cell counts using automated CBC analysis to identify potential acute promyelocytic leukemia (APL) using a convolutional neural network (CNN), which can eliminate the potential pitfalls of manual observation. Analyses of an unprecedented, realistic data set validated that the quantitative relationship between the CBC scattergram and an APL abnormality is highly consistent. This is the first study to date focusing on screening for APL using scattergrams of the difference in white blood cell counts from routine CBC tests and has significant clinical relevance. The authors recommend using this method even before analyzing cell images, which could provide the earliest way to screen for APL in a sensitive and accurate way.

Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.

Identification and haplotype analysis of SiCHLI: a gene for yellow-green seedling as morphological marker to accelerate foxtail millet (Setaria italica) hybrid breeding.

KEY MESSAGE: We cloned and developed functional markers for the SiCHLI gene, which is responsible for the yellow-green color of leaves in foxtail millet, a frequently used marker trait in the hybrid breeding of foxtail millet by using bulked segregant analysis sequencing and haplotype analysis on the F2 and core-collected nature populations. The color of leaves has been widely used as a marker for the hybrid breeding of foxtail millet; however, few related gene have been cloned to date. Here, we used two F2 populations generated from crosses between the highly male-sterile material 125A with yellow-green leaves, and CG58 and S410, which have green leaves, to identify the genes underlying the yellow-green color of the leaves of foxtail millet. The leaves of 125A seedlings were yellow-green, but they became green at the heading stage. The content of chlorophyll a and chlorophyll b was lower, the number of thylakoid lamellae and grana was reduced, and the chloroplasts was more rounded in 125A than in S410 at the yellow-green leaf stage; however, no differences were observed between 125A and S410 in these traits and photosynthetic at the heading stage. Bulked segregant analysis and map-based cloning revealed that the SiCHLI gene is responsible for the leaf colors of 125A. A nonsynonymous mutation (C/T) in exon 3 causes yellow-green leaves in 125A at the seedling stage. Haplotype analysis of the SiCHLI gene in 596 core collected accessions revealed a new haplotype associated with high photosynthetic metabolic potential at the heading and mature stages, which could be used to enhance sterile lines with yellow-green leaves. We developed a functional marker that will facilitate the identification of foxtail millet accessions with the different types of yellow-green leaves. Generally, our study provides new genetic resources to guide the future marker-assisted or target-base editing in foxtail millet hybrid breeding.

Experience of treating congenital complete atrioventricular block with epicardial pacemaker in infants and young children: a retrospective study.

BACKGROUND: This article summarizes the treatment experience for congenital complete atrioventricular block (CCAVB) in newborns and infants, and discusses the necessity and feasibility of treating CCAVB with permanent pacemaker implantation in this population. METHODS: In this study, the clinical data and follow-up results of nine children admitted at our center with CCAVB from January 2005 to March 2023 were retrospectively analyzed. Among them, two children received early implantation of permanent pacemakers (within 1 year of age), two children received non-early implantation (1 year or older), and the remaining five children received no pacemaker implantation. CCAVB diagnosis was confirmed by clinical symptoms and clinical examinations, including electrocardiography and echocardiography before surgery. After surgery, the pacing and sensing functions of the pacemaker were observed using electrocardiography, echocardiography, and pacing threshold monitoring. A comprehensive assessment of the treatment efficacy was conducted, encompassing improvements in clinical symptoms, growth and development, as well as the absence of any additional potential complications. The children who did not receive pacemaker implantation were followed up. RESULTS: Among the four children who successfully received pacemaker implantation, one child who received non-early implantation died. For the remaining three children, the threshold level, amplitude, impedance, and minute ventilation sensor function of the pacemaker were good during the follow-up period, with a heart rate at the pacing rate. The growth and development of the aforementioned patients who received pacemaker implantation demonstrated adherence to the percentile curve, and their motor and cognitive development remained unaffected. However, among the children who did not undergo pacemaker implantation, two experienced death, while three were lost to follow-up, thereby limiting the evaluation of their long-term outcomes. CONCLUSIONS: Early implantation of an epicardial pacemaker at an early stage in newborns and infants diagnosed with CCAVB can significantly improve clinical symptoms without affecting their growth and development. These data are in line with current literature and suggest that early implantation of an epicardial pacemaker in newborns and infants diagnosed with CCAVB but further studies are needed.

Comparative Inhibitory Effects of Natural Biflavones from Ginkgo against Human CYP1B1 in Recombinant Enzymes and MCF-7 Cells.

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.

Bleeding due to successive duodenal and rectal ulcers in an 81-year-old patient with severe COVID-19: a case report.

BACKGROUND: In the early stages of the coronavirus disease 2019 (COVID-19) outbreak, the most widely recognised symptoms of the disease were fever, cough, shortness of breath, myalgia, and fatigue. However, in addition to these symptoms, COVID-19 can cause systemic symptoms outside the lungs. Older patients with severe COVID-19 often require admission to the intensive care unit (ICU). Acute rectal ulcer bleeding, characterised by painless, profuse haematochezia, caused by solitary or multiple rectal ulcers, is one of the main causes of severe haematochezia in patients with COVID-19 in the ICU. However, recurrent duodenal ulcer bleeding followed by rectal ulcer bleeding has not previously been reported in older patients during ICU treatment for severe COVID-19. CASES PRESENTATION: Herein, we report the case of an 81-year-old woman admitted to the emergency department due to severe COVID-19 and transferred to the ICU 2 days later for treatment. During treatment in the ICU, the patient developed recurrent duodenal ulcer bleeding and underwent endoscopic electrocoagulation haemostasis and gastroduodenal artery embolisation. However, the night after the final haemostatic operation, due to rectal ulcer bleeding, the patient discharged bloody stools intermittently, which was effectively controlled using endoscopic electrocoagulation, topical medication, blood transfusion, and haemostatic drugs. CONCLUSIONS: To the best of our knowledge, this is the first report of duodenal ulcer bleeding followed by rectal ulcer bleeding in an older patient with severe COVID-19 infection. This report creates awareness for clinicians about the multiple and complex gastrointestinal symptoms that may occur during COVID-19 treatment.

Subdural osteoma in an adolescent patient with epilepsy: an unusual case report and literature review.

OBJECTIVE: Subdural osteoma (SO) is a rarely reported benign tumor, and there is no report of SO manifested with epileptic seizures. We aim to further the understanding of SO-related epilepsy. METHODS: Here, we report a meaningful case of epilepsy secondary to SO. A systematic review of the literature about SO using the electronic database PubMed and Web of science up to December 2022 was conducted. RESULTS: A 15-year-old girl presented with epileptic seizures for 8 years. Magnetic resonance imaging revealed an irregular lesion with heterogeneous signal in the right frontal convexity. Right frontal craniotomy was performed to remove the lesion. The pathological diagnosis was SO. Histological analysis revealed that the mechanosensitive ion channels Piezo 1/2 were upregulated in the brain tissue compressed by the osteoma, compared with the levels in the osteoma-free region. Seizure freedom was obtained during the 6-month follow-up after the surgery. We identified 24 cases of SO in 23 articles. With our case, a total of 25 cases with 32 SOs was included. Of 25 cases, 24 are adults, and 1 is a child. Seizure has been reported only in our case. Frontal osteoma was found in 76% of the patients. Symptoms were cured in 56% of the patients after surgery. CONCLUSION: Surgery is a safe and effective approach to the treatment of symptomatic osteoma. Mechanical compression on cerebral cortex may be a predisposing factor of the epileptogenesis caused by the SO.

Multivariate analysis of seizure outcomes after resective surgery for focal epilepsy: a single-center study on 833 patients.

The predictors of seizure outcomes after resective surgery for focal epilepsy, for an update on the features of good and poor outcomes, are investigated. A retrospective study of patients with focal epilepsy undergoing resective surgery from March 2011 to April 2019 was performed. There were 3 groups according to the seizure outcomes: seizure freedom, seizure improvement, and no improvement. Predictors of seizure outcomes were identified by multivariate logistic regression analysis. Of all 833 patients, 561 (67.3%) patients remained seizure-free at the last follow-up, 203 (24.4%) patients had seizure improvement, and 69 (8.3%) had no improvement. The mean follow-up duration was 5.2 years (range: 2.7 to 9.6). Predictors of better outcomes included epilepsy duration < 5 years, localized discharge, no. of antiepileptic drugs at surgery < 3, and temporal lobe resection. However, predictors of worse outcomes included intracranial hemorrhage in infancy, interictal abnormal discharge, intracranial electrode monitoring, and acute postoperative seizure. Our study suggests that resective surgery for focal epilepsy has satisfactory outcomes. Short epilepsy duration, localized discharge, and temporal lobe resection are positive predictors of seizure freedom. Patients with these predictors are intensively recommended for surgery.

Renal transporter OAT1 and PPAR-α pathway co-contribute to icaritin-induced nephrotoxicity.

This study aimed to investigate the potential nephrotoxicity of icaritin and the underlying mechanism by in vitro-in vivo experiment technology combined with proteomics technology. First, icaritin showed a significant cytotoxic effect on HK-2 cells, which was accompanied by increased LDH and TNF-α in the supernatant, decreased protein expressions of Bcl-2 and increased Bax and enhanced apoptosis of HK-2 cells as measured by TUNEL staining. Moreover, icaritin induced obvious tubular damage and up-regulation of BUN and CRE levels in plasma in mice. Second, intracellular uptake of icaritin was considerably higher in hOAT1-HEK293 cells than in mock-HEK293 cells, suggesting that icaritin might accumulate in renal cells via OAT1 uptake. Importantly, icaritin caused significant changes in the PPAR signaling pathway in HK2 cells through proteomic analysis. Then, in vitro and in vivo results verified that icaritin significantly downregulated the protein expression of PPAR-α as well as downregulated APOB, ACSL3, ACSL4, and upregulated 5/12/15-HETE, implying that a lipid metabolism disorder was involved in the icaritin-induced nephrotoxicity. Finally, icaritin was found to increase the accumulation of iron and LPO levels while reducing the activity of GPX4, suggesting that ferroptosis was involved in the nephrotoxicity induced by icaritin.

Anti-Postmenopausal osteoporosis effects of Isopsoralen: A bioinformatics-integrated experimental study.

Isopsoralen (IPRN), which comes from the fruit of Psoralea corylifolia, has been identified as a kind of phytoestrogen and has been proven to be effective for the treatment of osteoporosis (OP). However, the mechanisms underlying IPRN's anti-OP effects, especially the anti-postmenopausal osteoporosis (PMOP) effects, remain indistinct. Thus, this study aimed to investigate the effects and mechanisms of IPRN's anti-PMOP activity. In this study, the bioinformatics results predicted that IPRN could resist PMOP by targeting EGFR, AKT1, SRC, CCND1, ESR1 (ER-α), AR, PGR, BRCA1, PTGS2, and IGF1R. An ovariectomized (OVX) mice model and a H2 O2 -induced bone marrow mesenchyml stem cells (BMSCs) model confirmed that IPRN could inhibit the bone loss induced by OVX in mice and promote the osteogenic differentiation in H2 O2 -induced BMSCs by inhibiting oxidative stress and apoptosis. Moreover, IPRN could significantly produce the above effects by upregulating ESR1. IPRN might be a therapeutic agent for PMOP by acting as an estrogen replacement agent and a natural antioxidant.

Naringin protects against inflammation and apoptosis induced by intestinal ischemia-reperfusion injury through deactivation of cGAS-STING signaling pathway.

Effective amelioration of ischemia/reperfusion (I/R)-induced intestinal injury and revealing its mechanisms remain the challenges in both preclinic and clinic. Potential mechanisms of naringin in ameliorating I/R-induced intestinal injury remain unknown. Based on pre-experiments, I/R-injured rat intestine in vivo and hypoxia-reoxygenation (H/R)-injured IEC-6 cells in vitro were used to verify that naringin-alleviated I/R-induced intestinal injury was mediated via deactivating cGAS-STING signaling pathway. Naringin improved intestinal damage using hematoxylin and eosin staining and decreased alanine aminotransferase and aspartate aminotransferase contents in plasma. Naringin decreased inflammation characterized by reducing IL-6, IL-1ß, TNF-α, and IFN-ß contents in both plasma and IEC-6 cells. Naringin mitigated oxidative stress via recovering superoxide dismutase, glutathione, and malondialdehyde levels in the I/R-injured intestine. Naringin reduced the expression of apoptotic proteins, including Bax, caspase-3, and Bcl-2, and reduced terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells both in vivo and in vitro, and decreased Hoechst 33342 signals in vitro. cGAS, STING, p-TBK1, p-IRF3, and NF-κB expressions were up-regulated both in vivo and in vitro respectively and the up-regulated indexes were reversed by naringin. Transfection of cGAS-siRNA and cGAS-cDNA significantly down-regulated and up-regulated cGAS-STING signaling-related protein expressions, respectively, and partially weakened naringin-induced amelioration on these indexes, suggesting that deactivation of cGAS-STING signaling is the crucial target for naringin-induced amelioration on I/R-injured intestine.

The clinical features of patients with seizure freedom and failure after total corpus callosotomy for childhood-onset refractory epilepsy.

BACKGROUND: Corpus callosotomy is a palliative surgery for medically refractory epilepsy. We aim to analyze the clinical features of patients with seizure freedom and failure after total corpus callosotomy for childhood-onset refractory epilepsy. METHODS: We retrospectively reviewed the clinical courses of patients with childhood-onset refractory epilepsy undergoing total corpus callosotomy between May 2009 and March 2019. Seizure outcome at the last follow-up was the primary outcome. The clinical features of patients with seizure freedom and failure after callosotomy were compared. RESULTS: Eighty patients with childhood-onset refractory epilepsy underwent total corpus callosotomy; 15 (18.8%) obtained freedom from all seizures and 19 (23.8%) had unworthwhile improvement and failure. The mean ages at seizure onset in patients with seizure freedom and failure after callosotomy were 5.7 and 5.9 years; and mean seizure durations were 9.4 and 11.5 years, respectively. Univariate analysis found epilepsy syndrome (p = 0.047), mental retardation (p = 0.007), previous medical history (p = 0.004), ≥10 seizures per day (p = 0.024), theta waves in the background electroencephalogram (p = 0.024), and acute postoperative seizure (p = 0.000) were associated with failure after callosotomy. Seizure freedom after callosotomy was more common among patients with less than 10 seizures per day. CONCLUSIONS: Total corpus callosotomy is an effective palliative procedure for childhood-onset refractory epilepsy, particularly for patients with specific clinical characteristics. Callosotomy has a high seizure-free rate in well-selected patients.

Genome-Wide Characterization and Haplotypic Variation Analysis of the YUC Gene Family in Foxtail Millet (Setaria italica).

Panicle development and grain production in crop species are essential breeding characteristics affected by the synthesis of auxin, which is influenced by flavin monooxygenase-encoding genes such as YUC (YUCCA) family members. In this trial, fourteen YUCs were identified and named uniformly in foxtail millet, an ancient crop species cultivated across the world. The phylogenetic analysis revealed that the SiYUCs were clustered into four subgroups; protein motif and gene structure analyses suggested that the closely clustered SiYUC genes were relatively conserved within each subgroup; while genome mapping analysis indicated that the SiYUC genes were unevenly distributed on foxtail millet chromosomes and colinear with other grass species. Transcription analysis revealed that the SiYUC genes differed greatly in expression pattern in different tissues and contained hormonal/light/stress-responding cis-elements. The haplotype characterization of SiYUC genes indicated many superior haplotypes of SiYUCs correlated with higher panicle and grain weight could be favorably selected by breeding. These results will be useful for the further study of the functional characteristics of SiYUC genes, particularly with regard to the marker-assisted pyramiding of beneficial haplotypes in foxtail millet breeding programs.

[Anemoside B4 regulates fatty acid metabolism reprogramming in mice with colitis-associated cancer].

The study aimed to investigate the effect of anemoside B4(B4) on fatty acid metabolism in mice with colitis-associated cancer(CAC). The CAC model was established by azoxymethane(AOM)/dextran sodium sulfate(DSS) in mice. Mice were randomly divided into a normal group, a model group, and low-, medium-, and high-dose anemoside B4 groups. After the experiment, the length of the mouse colon and the size of the tumor were measured, and the pathological alterations in the mouse colon were observed using hematoxylin-eosin(HE) staining. The slices of the colon tumor were obtained for spatial metabolome analysis to analyze the distribution of fatty acid metabolism-related substances in the tumor. The mRNA levels of SREBP-1, FAS, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 were determined by real-time quantitative PCR(RT-qPCR). The results revealed that the model group showed decreased body weight(P<0.05) and colon length(P<0.001), increased number of tumors, and increased pathological score(P<0.01). Spatial metabolome analysis revealed that the content of fatty acids and their derivatives, carnitine, and phospholipid in the colon tumor was increased. RT-qPCR results indicated that fatty acid de novo synthesis and ß-oxidation-related genes, such as SREBP-1, FASN, ACCα, SCD-1, ACOX, UCP-2, and CPT-1 mRNA expression levels increased considerably(P<0.05, P<0.001). After anemoside B4 administration, the colon length increased(P<0.01), and the number of tumors decreased in the high-dose anemoside B4 group(P<0.05). Additionally, spatial metabolome analysis showed that anemoside B4 could decrease the content of fatty acids and their derivatives, carnitine, and phospholipids in colon tumors. Meanwhile, anemoside B4 could also down-regulate the expression of FASN, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 in the colon(P<0.05, P<0.01, P<0.001). The findings of this study show that anemoside B4 may inhibit CAC via regulating fatty acid metabolism reprogramming.

Tailored Sitting Tai Chi Program for Subacute Stroke Survivors: A Randomized Controlled Trial.

BACKGROUND: The initiation of exercise during rehabilitation at the subacute stage could provide stroke survivors with an approach to recovery that capitalizes on unique physiological conditions and promotes spontaneous recovery. We aimed to examine the effects of a tailored sitting Tai Chi program on recovery outcomes among subacute stroke survivors. METHODS: We conducted a 12-week assessor-blind randomized controlled trial in China. Subacute stroke survivor-caregiver dyads were recruited and randomly assigned to either the sitting Tai Chi group (n=80) or attention control group (n=80). Outcomes including upper limb function (Fugl-Meyer Assessment Upper Extremity & Wolf Motor Function Test), balance control (Berg Balance Scale), sitting balance control (Trunk Impairment Scale), depressive symptoms (Geriatric Depression Scale Short Form), shoulder range of motion, shoulder pain (ShoulderQ), activities of daily living (Modified Barthel Index), and quality of life (Stroke Specific Quality of Life Scale) were measured at baseline, in-process, immediately post, and 4-week postintervention. RESULTS: Immediately postintervention, the sitting Tai Chi group (n=69) showed significant upper limb function improvement in the primary outcomes including the performance time (regression coefficient of the group-by-time interaction, B=-21.415 [95% CI, -31.000 to -11.831]) and functional ability (B=10.146 [95% CI, 4.886-15.406]) domains of the Wolf Motor Function Test, balance control (B, 4.972 [95% CI, 1.356-8.588]), and sitting balance control (B=4.397 [95% CI, 2.699-6.096]). Compared with the control group (n=65), improvements were also observed in secondary outcomes including depressive symptoms (B=-1.626 [95% CI, -2.304 to -0.948]), shoulder extension (B=4.518 [95% CI, 0.893-8.144]), activities of daily living (B=5.510 [95% CI, 0.450-10.569]), and quality of life (B=15.680 [95% CI, 7.255-24.105]). CONCLUSIONS: The results support the effectiveness of a tailored sitting Tai Chi program in improving recovery outcomes among subacute stroke survivors and provide additional knowledge to support the clinical implementation of such a program. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04138407.