Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS.

High levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully characterized. Here, we report that protein demethylase PHF8 is overexpressed in many types of cancers, including colon and lung cancer, and is negatively correlated with ETC gene expression. While it is well known to demethylate histones to activate transcription, PHF8 demethylates transcription factor YY1, functioning as a co-repressor for a large set of nuclear-coded ETC genes to drive mROS production and cancer development. In addition to genetically ablating PHF8, pharmacologically targeting PHF8 with a specific chemical inhibitor, iPHF8, is potent in regulating YY1 methylation, ETC gene transcription, mROS production, and cell growth in colon and lung cancer cells. iPHF8 exhibits potency and safety in suppressing tumor growth in cell-line- and patient-derived xenografts in vivo. Our data uncover a key epigenetic mechanism underlying ETC gene transcriptional regulation, demonstrating that targeting the PHF8/YY1 axis has great potential to treat cancers.

MDSCs are important osteoclast precursors primed by B cells in rheumatoid arthritis.

Osteoclast-mediated bone erosion and deformation represent significant pathological features in rheumatoid arthritis (RA). Myeloid-derived suppressor cells (MDSCs) and B cells have emerged as key contributors to the progression of RA. Nevertheless, their involvement, especially the interaction in RA osteoclastogenesis remains elusive. In this study, our results revealed a marked expansion of MDSCs in RA patients, and importantly, their abundance was positively correlated with radiographic damage evaluated by the Sharp/van der Heijde score. Notably, MDSCs derived from both RA patients and arthritic mice exhibited a heightened propensity to differentiate into osteoclasts compared with those from healthy individuals. Intriguingly, we observed that B cells from RA patients could augment the osteoclastogenic potential of MDSCs, which was also observed in arthritic mice. The impact of B cells on MDSC-mediated osteoclastogenesis was found to be most pronounced in switched memory B cells, followed by CD21low B cells and naïve B cells. MDSCs from B-cell-deficient mice exhibited diminished capacity to differentiate into osteoclasts, accompanied by distinct gene expression profiles associated with osteoclastogenesis. Taken together, our findings suggested that MDSCs were important osteoclast precursors primed by B cells in RA, serving as novel therapeutic targets for the persistent disease.

IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures.

BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations. RESULTS: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients. CONCLUSIONS: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.

Highly Selective O-Phenylene Bisurea Catalysts for ROP: Stabilization of Oxyanion Transition State by a Semiflexible Hydrogen Bond Pocket.

Organocatalyzed ring-opening polymerization (ROP) is a versatile technique for synthesizing biodegradable polymers, including polyesters and polycarbonates. We introduce o-phenylene bisurea (OPBU) (di)anions as a novel class of organocatalysts that are fast, easily tunable, mildly basic, and exceptionally selective. These catalysts surpass previous generations, such as thiourea, urea, and TBD, in selectivity (kp/ktr) by 8 to 120 times. OPBU catalysts facilitate the ROP of various monomers, achieving high conversions (>95%) in seconds to minutes, producing polymers with precise molecular weights and very low dispersities (D ≈ 1.01). This performance nearly matches the ideal distribution expected from living polymerization (Poisson distribution). Density functional theory (DFT) calculations reveal that the catalysts stabilize the oxyanion transition state via a hydrogen bond pocket similar to the "oxyanion hole" in enzymatic catalysis. Both experimental and theoretical analyses highlight the critical role of the semirigid o-phenylene linker in creating a hydrogen bond pocket that is tight yet flexible enough to accommodate the oxyanion transition state effectively. These new insights have provided a new class of organic catalysts whose accessibility, moderate basicity, excellent solubility, and unparalleled selectivity and tunability open up new opportunities for controlled polymer synthesis.

Upregulation of hsa-miR-141-3p promotes uterine cervical carcinoma progression via targeting dual-specificity protein phosphatase 1.

We aimed to explore the aberrant expression status of hsa-miR-141-3p and dual-specificity protein phosphatase 1 (DUSP1) and their relative mechanisms in uterine cervical carcinoma (UCC).Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was conducted to detect the expression of hsa-miR-141-3p. Immunohistochemical (IHC) staining was performed to examine the expression of DUSP1 in UCC. Gene chips and RNA-seq datasets were also obtained to assess the expression level. Integrated standardized mean difference (SMD) was calculated to evaluate the expression status of hsa-miR-141-3p in UCC tissues comprehensively. DUSP1-overexpression and hsa-miR-141-3p-inhibition HeLa cells were established, and CCK-8, transwell, wound healing, cell cycle, and apoptosis assays were implemented. The targets of hsa-miR-141-3p were obtained with online tools, and the combination of hsa-miR-141-3p and DUSP1 was validated via dual-luciferase reporter assay. Single-cell RNA-seq data were analyzed to explore hsa-miR-141-3p and DUSP1 in different cells. An integrated SMD of 1.41 (95% CI[0.45, 2.38], p = 0.0041) with 558 samples revealed the overexpression of hsa-miR-141-3p in UCC tissues. And the pooled SMD of -1.06 (95% CI[-1.45, -0.66], p < 0.0001) with 1,268 samples indicated the downregulation of DUSP1. Inhibition of hsa-miR-141-3p could upregulate DUSP1 expression and suppress invasiveness and metastasis of HeLa cells. Overexpression of DUSP1 could hamper proliferation, invasion, and migration and boost apoptosis and distribution of G1 phase. The dual-luciferase reporter assay validated the combination of hsa-miR-141-3p and DUSP1. Moreover, the targets of hsa-miR-141-3p were mainly enriched in the MAPK signaling pathway and activated in fibroblasts and endothelial cells. The current study illustrated the upregulation of hsa-miR-141-3p and the downregulation of DUSP1 in UCC tissues. Hsa-miR-141-3p could promote UCC progression by targeting DUSP1.

The protocol of enhanced recovery after cardiac surgery in adult patients: A stepped wedge cluster randomized trial.

BACKGROUND: The enhanced recovery after cardiac surgery is a bundle of measurements from preoperative to postoperative phases to improve patients' recovery. METHODS: This study is a multicenter, stepwise design, cluster randomized controlled trial. About 3,600 patients presenting during control and intervention periods are eligible if they are aged from 18 to 80 years old awaiting elective cardiac surgery with cardiopulmonary bypass (CPB). About 5 centers are randomly assigned to staggered start dates for one-way crossover from the control phase to the intervention phase. In the intervention periods, patients will receive ERAS strategy including preoperative, intraoperative, and postoperative approaches. During the control phase, patients receive usual care. The primary outcome consists of major adverse cardiac and cerebrovascular events (MACCEs), postoperative pulmonary complications (PPCs), and acute kidney injury (AKI). DISCUSSION: This study aims to compare the application of ERAS management protocol and traditional management protocol in adult cardiac surgery under extracorporeal circulation.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

STOP1 activates NRT1.1-mediated nitrate uptake to create a favorable rhizospheric pH for plant adaptation to acidity.

Protons (H+) in acidic soils arrest plant growth. However, the mechanisms by which plants optimize their biological processes to diminish the unfavorable effects of H+ stress remain largely unclear. Here, we showed that in the roots of Arabidopsis thaliana, the C2H2-type transcription factor STOP1 in the nucleus was enriched by low pH in a nitrate-independent manner, with the spatial expression pattern of NITRATE TRANSPORTER 1.1 (NRT1.1) established by low pH required the action of STOP1. Additionally, the nrt1.1 and stop1 mutants, as well as the nrt1.1 stop1 double mutant, had a similar hypersensitive phenotype to low pH, indicating that STOP1 and NRT1.1 function in the same pathway for H+ tolerance. Molecular assays revealed that STOP1 directly bound to the promoter of NRT1.1 to activate its transcription in response to low pH, thus upregulating its nitrate uptake. This action improved the nitrogen use efficiency (NUE) of plants and created a favorable rhizospheric pH for root growth by enhancing H+ depletion in the rhizosphere. Consequently, the constitutive expression of NRT1.1 in stop1 mutants abolished the hypersensitive phenotype to low pH. These results demonstrate that STOP1-NRT1.1 is a key module for plants to optimize NUE and ensure better plant growth in acidic media.

The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up.

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

Prognostic factors in patients with secondary hemophagocytic lymphohistioc ytosis in a Chinese cohort.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome with high mortality mediated by an unbridled and persistent activation of cytotoxic T lymphocytes and natural killer cells. However, the influence factors of early death in adult sHLH patients are still not fully elucidated, which need further investigating. We have conducted an observational study of adult HLH patients between January 2016 and December 2022. All patients are enrolled according to HLH-2004 criteria. Clinical manifestations, laboratory data, treatments, and outcomes have been recorded. Influence factors associated with prognosis are calculated by using logistic regression models. Overall, 220 patients enrolled in this study. The etiologies of HLH were divided into five groups including autoimmune-associated hemophagocytic syndrome (AAHS) (n = 90, 40.9%), malignancies (n = 73, 33.2%), EBV-HLH (n = 18, 8.2%), infection excluded EBV (n = 24, 10.9%), and other triggers (n = 15, 6.8%). Among them, EBV-HLH had the highest mortality (77.8%), and AAHS had the lowest mortality (14.4%). Multivariate analysis indicated that age (≥ 38 years old), cytopenia ≥ 2 lines, platelets (≤ 50 × 109/L), aspartate aminotransferase (≥ 135U/L), prothrombin time (≥ 14.9 s) and activated partial thromboplastin time (≥ 38.5s), EBV, and fungal infection are independent risk factors for poor prognosis of HLH. Adult HLH patients with elder age, cytopenia ≥ 2 lines, levels of decreased platelets, increased AST, prolonged PT and APTT, EBV, and fungal infection tend to have a poor prognosis.

A real-world prospective observational study of eptinezumab in Asian patients with migraine.

OBJECTIVE: To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. METHODS: This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. RESULTS: Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. CONCLUSION: Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.

Diastereomers of Steroidal Alkaloids with Cytotoxic Activities against Non-Small-Cell Lung Cancer from the Bulbs of Fritillaria sinica.

Eleven new steroidal alkaloids, along with nine known related compounds, were isolated from the bulbs of Fritillaria sinica. Seven pairs of diastereomers were identified, including six and four 20-deoxy cevanine-type steroidal alkaloid diastereomers with molecular weights of 413 and 415, respectively. Structures were elucidated based on spectroscopic data analysis, chemical derivatization, and single-crystal X-ray diffraction analysis. Compounds 5, 9, 11, 12, 16, and 20 exhibited significant in vitro cytotoxic activity against non-small-cell lung cancer with CC50 values from 6.8 ± 3.9 to 12 ± 5 µM.

Clinical characteristics of 217 Chinese cases with depersonalization/derealization disorder.

Depersonalization/derealization disorder (DPD) is a prevalent yet inadequately understood clinical condition characterized by a recurrent or persistent sense of unreality. This study aims to provide insight into DPD through descriptive and comparative analyses involving a large group of Chinese participants. The socio-demographic details (age, gender proportion, education, occupational status, marital status), depersonalized and dissociative symptom characteristics (symptomatic factors or subscales of the Cambridge Depersonalization Scale and the Dissociative Experiences Scale), development trajectory (age of onset, potential precipitating factors, course characteristics), treatment history (duration of delayed healthcare attendance, duration of delayed diagnosis, previous diagnoses), and adverse childhood experiences of the DPD patients are presented. Comparisons of anxiety and depressive symptoms, alongside psychosocial functioning, between DPD participants and those diagnosed with generalized anxiety disorder, bipolar disorders, and major depressive disorder were conducted. The analysis highlights a higher male preponderance and early onset of DPD, symptomatology marked by derealization, notable impairment in psychosocial functioning, and prolonged periods of delayed healthcare attendance and diagnosis associated with symptom severity. Furthermore, noteworthy relationships between adverse childhood experiences and symptom levels were identified. The findings substantiate the view that DPD is a serious but neglected mental disorder, urging initiatives to improve the current condition of DPD patients.

Integrative proteomics and metabolomics data analysis exploring the mechanism of brain injury after cardiac surgery in chronic stress rats.

OBJECTIVE: Preoperative chronic stress (CS) is associated with postoperative brain injury in patients undergoing open heart cardiac surgery. This research is to explore the potential molecular biological mechanisms of brain damage following cardiac surgery in preoperative CS rats by the analyses combining proteomics and metabolomics. METHODS: We constructed the chronic unpredictable stress (CUS) and cardiac surgery models in adult rats. We proved the brain injury in CUS cardiac surgery rats by Hematoxylin-Eosin (H&E) staining, followed by separating the hippocampal tissue and investigating the potential mechanisms of brain injury by the methods of data-independent acquisition proteomics and untargeted metabolomics. RESULTS: The signaling pathways of glycoproteins and metabolism of amino acids were the main possible mechanisms of brain injury in CUS rats following cardiac surgery according to the proteomics and metabolomics. In addition, the pathways of animo acids metabolism such as the pathways of lysine degradation and ß-alanine metabolism may be the main mechanism of cardiac surgery related brain injury in preoperative CUS rats. CONCLUSIONS: The pathways of animo acids metabolism such as lysine degradation and ß-alanine metabolism may be the potential mechanisms of brain injury in CUS rats following cardiac surgery. We should focus on the varieties of bioproteins and metabolites in these pathways, and related changes in other signaling pathways induced by the two pathways.

Predictors of length of hospital stay after pediatric Ebstein anomaly corrective surgery: a retrospective cohort study.

BACKGROUND: The remarkable advancements in surgical techniques over recent years have shifted the clinical focus from merely reducing mortality to enhancing the quality of postoperative recovery. The duration of a patient's hospital stay serves as a crucial indicator in evaluating postoperative recovery and surgical outcomes. This study aims to identify predictors of the length of hospital stay for children who have undergone corrective surgery for Ebstein Anomaly (EA). METHODS: We conducted a retrospective cohort study on children (under 18 years of age) diagnosed with EA who were admitted for corrective surgery between January 2009 and November 2021 at Fuwai Hospital. The primary outcome was the Time to Hospital Discharge (THD). Cox proportional hazard models were utilized to identify predictors of THD. In the context of time-to-event analysis, discharge was considered an event. In cases where death occurred before discharge, it was defined as an extended THD, input as 100 days (exceeding the longest observed THD), and considered as a non-event. RESULTS: A total of 270 children were included in this study, out of which three died in the hospital. Following the Cox proportional hazard analysis, six predictors of THD were identified. The hazard ratios and corresponding 95% confidence intervals were as follows: age, 1.030(1.005,1.055); C/R > 0.65, 0.507(0.364,0.707); Carpentier type C or D, 0.578(0.429,0.779); CPB time, 0.995(0.991,0.998); dexamethasone, 1.373(1.051,1.795); and transfusion, 0.680(0.529,0.875). The children were categorized into three groups based on the quartile of THD. Compared to children in the ≤ 6 days group, those in the ≥ 11 days group were associated with a higher incidence of adverse outcomes. Additionally, the duration of mechanical ventilation and ICU stay, as well as hospital costs, were significantly higher in this group. CONCLUSION: We identified six predictors of THD for children undergoing corrective surgery for EA. Clinicians can utilize these variables to optimize perioperative management strategies, reduce adverse complications, improve postoperative recovery, and reduce unnecessary medical expenses.

The protocol of Enhanced Recovery After Cardiac Surgery (ERACS) in congenital heart disease: a stepped wedge cluster randomized trial.

BACKGROUND: The Enhanced Recovery After Cardiac Surgery (ERACS) programs are comprehensive multidisciplinary interventions to improve patients' recovery. The application of the ERAS principle in pediatric patients has not been identified completely. METHODS: This study is a multicenter, stepwise design, cluster randomized controlled trial. 3030 patients presenting during control and intervention periods are eligible if they are aged from 28 days to 6 years old and awaiting elective correction surgery of congenital heart disease with cardiopulmonary bypass. 5 centers are randomly assigned to staggered start dates for one-way crossover from the control phase to the intervention phase. In the intervention periods, patients will receive a bundle strategy including preoperative, intraoperative, and postoperative approaches. During the control phase, patients receive the usual care. The primary outcome consists of major adverse cardiac and cerebrovascular events (MACCEs), postoperative pulmonary complications (PPCs), and acute kidney injury (AKI). DISCUSSION: This study aims to explore whether the bundle of ERAS measurements could improve patients' recovery in congenital heart surgery. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov . (NCT05914103).

G-quadruplex structural variations in human genome associated with single-nucleotide variations and their impact on gene activity.

G-quadruplexes (G4s) formed by guanine-rich nucleic acids play a role in essential biological processes such as transcription and replication. Besides the >1.5 million putative G-4-forming sequences (PQSs), the human genome features >640 million single-nucleotide variations (SNVs), the most common type of genetic variation among people or populations. An SNV may alter a G4 structure when it falls within a PQS motif. To date, genome-wide PQS-SNV interactions and their impact have not been investigated. Herein, we present a study on the PQS-SNV interactions and the impact they can bring to G4 structures and, subsequently, gene expressions. Based on build 154 of the Single Nucleotide Polymorphism Database (dbSNP), we identified 5 million gains/losses or structural conversions of G4s that can be caused by the SNVs. Of these G4 variations (G4Vs), 3.4 million are within genes, resulting in an average load of >120 G4Vs per gene, preferentially enriched near the transcription start site. Moreover, >80% of the G4Vs overlap with transcription factor-binding sites and >14% with enhancers, giving an average load of 3 and 7.5 for the two regulatory elements, respectively. Our experiments show that such G4Vs can significantly influence the expression of their host genes. These results reveal genome-wide G4Vs and their impact on gene activity, emphasizing an understanding of genetic variation, from a structural perspective, of their physiological function and pathological implications. The G4Vs may also provide a unique category of drug targets for individualized therapeutics, health risk assessment, and drug development.

Functionalized graphene oxide as a nanocarrier for delivering oridonin to improve anti-breast cancer cell activity.

In this study, a targeted nanocarrier was developed by functionalizing graphene oxide with polyethyleneimine and folic acid, intended for loading oridonin. The nanocarrier was successfully synthesized and characterized using an ultraviolet spectrum, Fourier transform infrared spectroscopy and scanning electron microscopy. The nanocarrier demonstrated a remarkable oridonin loading capacity, reaching 424.8 µg/mg, as determined by ultra-high performance liquid chromatography. In vitro drug release experiments exhibited a pH-dependent release profile, with a higher cumulative release in an acidic environment. The release mechanism followed the Ritger-Peppas equation model. Cytotoxicity assays indicated minimal toxicity of the nanocarrier. Enhanced cellular uptake by MCF7 cells was observed for carriers functionalized with folate and polyethyleneimine. These findings highlight the potential of functionalized graphene oxide as a promising carrier for oridonin delivery in biomedical applications.

Short-chain fatty acids mitigate Methamphetamine-induced hepatic injuries in a Sigma-1 receptor-dependent manner.

Methamphetamine (Meth) is a potent psychostimulant with well-established hepatotoxicity. Gut microbiota-derived short-chain fatty acids (SCFAs) have been reported to yield beneficial effects on the liver. In this study, we aim to further reveal the mechanisms of Meth-induced hepatic injuries and investigate the potential protective effects of SCFAs. Herein, mice were intraperitoneally injected with 15 mg/kg Meth to induce hepatic injuries. The composition of fecal microbiota and SCFAs was profiled using 16 S rRNA sequencing and Gas Chromatography/Mass Spectrometry (GC/MS) analysis, respectively. Subsequently, SCFAs supplementation was performed to evaluate the protective effects against hepatic injuries. Additionally, Sigma-1 receptor knockout (S1R-/-) mice and fluvoxamine (Flu), an agonist of S1R, were introduced to investigate the mechanisms underlying the protective effects of SCFAs. Our results showed that Meth activated S1R and induced hepatic autophagy, inflammation, and oxidative stress by stimulating the MAPK/ERK pathway. Meanwhile, Meth disrupted SCFAs product-related microbiota, leading to a reduction in fecal SCFAs (especially Acetic acid and Propanoic acid). Accompanied by the optimization of gut microbiota, SCFAs supplementation normalized S1R expression and ameliorated Meth-induced hepatic injuries by repressing the MAPK/ERK pathway. Effectively, S1R knockout repressed Meth-induced activation of the MAPK/ERK pathway and further ameliorated hepatic injuries. Finally, the overexpression of S1R stimulated the MAPK/ERK pathway and yielded comparable adverse phenotypes to Meth administration. These findings suggest that Meth-induced hepatic injuries relied on the activation of S1R, which could be alleviated by SCFAs supplementation. Our study confirms the crucial role of S1R in Meth-induced hepatic injuries for the first time and provides a potential preemptive therapy.