The impact of lipidome on breast cancer: a Mendelian randomization study.

OBJECTIVE: This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method. METHOD: The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study. RESULTS: By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER+ BC), phosphatidylcholine (P < 0.05) and phosphatidylinositol (OR: 0.916-0.966, P < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P < 0.001) and triacylglycerol, OR: 0.894-0.960, P < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ER+BC. In the case of estrogen receptor-negative BC (ER- BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P = 0.008), and glycerolipids (OR = 0.909, P = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034-1.056, P < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091-1.119, P < 0.05) was an important causal effect in ER-BC. CONCLUSIONS: The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.

Bimetallic H2 Addition and Intramolecular Caryl-H Activation Mediated by an Iron-Zinc Hydride.

Heteronuclear Fe(µ-H)Zn hydride Cp*Fe(1,2-Cy2PC6H4)HZnEt (3) undergoes reversible intramolecular Caryl-H reductive elimination through coupling of the cyclometalated phosphinoaryl ligand and the hydride, giving rise to a formal Fe(0)-Zn(II) species. Addition of CO intercepts this equilibrium, affording Cp*(Cy2PPh)(CO)Fe-ZnEt that features a dative Fe-Zn bond. Significantly, this system achieves bimetallic H2 addition, as demonstrated by the transformation of the monohydride Fe(µ-H)Zn to a deuterated dihydride Fe-(µ-D)2-Zn upon reaction with D2.

Exploring the NRF2-TP53 Signaling Network Through Machine Learning and Pan-Cancer Analysis: Identifying Potential targets for Cancer Prognosis Related to Oxidative Stress.

Oxidative stress (OXS) is closely related to tumor prognosis and immune response, while TP53 integrated with NRF2 is closely associated with the regulation of cancer-related OXS. Hence, constructing a TP53-NRF2 integrated OXS signature of pan-cancer is essential in predicting survival prognosis and facilitating cancer drug treatment. The pan-cancer analysis acquired the Cancer Genome Atlas (TCGA) transcriptome sequencing data from UCSC Xena, which consisted of 33 cancer types (n = 10 440). The Random Forest, Lasso regression, and Cox regression analyses are used to construct an OXS score based on 25 OXS genes. Following this, based on the OXS signature, patients are categorized into low- and high-risk groups. The disparities between the two cohorts regarding survival prognosis, immune infiltration, and drug sensitivity are delved deeply. The expression level of genes is confirmed using immunohistochemistry. The prognosis of pan-cancer patients is adequately predicted by the OXS signature with the assistance of the machine-learning algorithm. A highly accurate nomogram is developed by combining the OXS signature and clinical features. The presence of immune cells indicated that the OXS signature can be associated with the critical pathways of immunotherapy for all types of cancer, and BCL2 showed promising results. Distinct inter-group differences are observed in the OXS signature for frequently utilized antineoplastic medications in clinical settings, including first-line drugs suggested in the guidelines. In summary, by conducting a thorough analysis of OXS genes, a new model based on OXSscore is successfully developed. This model can predict the clinical prognosis and drug sensitivity of pan-cancer with high accuracy. Potential stars in the field of cancer-related anti-OXS may include drugs that target BCL2.

The moderating effects of parental psychological control on the relationship between unsociability and socio-emotional functioning among Chinese children.

Introduction: There have been studies indicating that children's unsociability was associated with poorer socio-emotional functioning in China. Although some researchers have found that parenting behavior would influence the relationship between children's unsociability and adjustment, the role of parental psychological control has not been explored. This study aimed to investigate the moderating effect of parental psychological control on the relationship between unsociability and socio-emotional functioning in Chinese children. Methods: A total of 1,275 students from Grades 3 to 7 (637 boys, Mage = 10.78 years, SD = 1.55 years) were selected from four public schools in Shanghai to participate in this study. Data of unsociability, peer victimization and social preference were collected from peer-nominations, and data of parental psychological control, depressive symptoms and social anxiety were collected from self-reports. Results: There were positive associations between unsociability and peer victimization, depressive symptoms, and social anxiety, as well as a negative association between unsociability and social preference. Parental psychological control moderated these associations, specifically, the associations between unsociability and peer victimization, social preference, and depressive symptoms were stronger, and the association between unsociability and social anxiety was only significant among children with higher level of parental psychological control. Discussion: The findings in the current study highlight the importance of parental psychological control in the socio-emotional functioning of unsociable children in the Chinese context, enlightening educators that improving parenting behavior is essential for children's development.

Single-cell and whole-transcriptome sequencing of lymph node metastasis-related gene signature: A large-scale pan-cancer cohort, machine learning and experimental study.

BACKGROUND: Lymph node metastasis (LNM) is an independent prognostic factor in numerous types of cancer. Therefore, a LNM-related gene-based nomogram may precisely predict survival and drug sensitivity, and reveal the mechanism underlying LNM. MATERIALS AND METHODS: Gene sequencing profiles of pan-cancer data (33 cancer types) were acquired from The Cancer Genome Atlas UCSC Xena database. Patients were classified into primary (N = 10,071) and testing (N = 5,036) cohorts. The lymph node score (LNscore) was established via single-cell RNA sequencing, whole-transcriptome sequencing, machine learning, and Cox regression analyses. A novel prognosis model, formulated by incorporating the LNscore and clinical characteristics, was evaluated using the concordance index, calibration curve, and decision curve analysis. Moreover, patients were assigned into high- and low-risk groups according to the median LNscore. We investigated these two groups for survival prognosis, functional enrichment, immune infiltration, and drug sensitivity. In addition, we silenced and overexpressed insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). We also analyzed the behavior of breast cancer (BRCA) cells regarding lymphatic metastasis and lymphangiogenesis in vitro. IGF2BP2 stimulated the proliferation of BRCA cells via 5-Ethynyl-2'-deoxyuridine and Cell Counting Kit-8 experiments. RESULTS: A LNM-related set of 12 genes was identified and utilized to determine the LNscore. The concordance-index of both cohorts in the LNscore-based model was >0.7. The immune landscape revealed that the sensitivity to immunotherapy might be better in the high-risk group versus the low-risk group. In addition, we discovered that IGF2BP2 was overexpressed in BRCA tissues and significantly associated with poor survival. Functional analysis indicated that IGF2BP2 promoted BRCA cell migration and proliferation. Additionally, IGF2BP2 accelerated lymphatic metastasis and lymphangiogenesis in vivo. CONCLUSIONS: A novel LNscore-based model was established via comprehensive analysis of LNM-related genes. This model can accurately predict patient survival and drug sensitivity, and reveal the mechanism of LNM in the pan-cancer setting.

Glycyrrhizin attenuates myocardial ischemia reperfusion injury by suppressing Inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway.

Ferroptosis, a form of regulated cell death process, play an important role in myocardial ischemia‒reperfusion (I/R) injury. Glycyrrhizin (GL), a natural glycoconjugate triterpene, has the property to improve growth rate, immune regulation, antioxidant, anti-inflammatory. However, whether GL can attenuate myocardial I/R injury by modulating ferroptosis or other mechanisms are still unclear. In this study, SD rats underwent in vivo myocardial ischemia/reperfusion (I/R) surgery, while H9C2 cells were subjected to the hypoxia/reoxygenation (H/R) model for in vitro experiments. In addition, TAK-242, a TLR4-specific antagonist, and GL were also used to evaluate the effect and mechanisms of GL on the cardiac function and expression of ferroptosis-related gene and protein in vivo and vitro. The results show that GL decreased not only the expression of the inflammation-related factors (HMGB1, TNF-α, IL-6, IL-18 and IL-1ß), but also reduced the number of TUNEL-positive cardiomyocytes, and mitigated pathological alterations in I/R injury. In addition, GL decreased the levels of MDA, promoted antioxidant capacity such as GSH, CAT, Cu/Zn-SOD, Mn-SOD, and SOD in vivo and vitro. More importantly, GL and TAK-242 regulate ferroptosis-related protein and gene expression in I/R and H/R model. Surprisingly, GL may ameliorate cardiomyocyte ferroptosis and ultimately improves cardiac function induced by H/R via the HMGB1-TLR4-GPX4 axis. Therefore, we have highlighted a novel mechanism by which GL regulates inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway to prevent myocardial I/R injury. GL appears to be a potentially applicable drug for the treatment of myocardial I/R injury.

[Left Main Trunk Orifice Reconstruction Using Aortic flap and Autologous Pulmonary Arterial Patch for Severe Left Main Trunk Stenosis After Arterial Switch Operation].

A 6-year-old boy with left main trunk (LMT) stenosis, who had undergone arterial switch operation (ASO) for transposition of the great arteries( TGA) before 6 years, underwent LMT orifice reconstruction. Coronary angiography showed severe stenosis of LMT, already when he was hospitalized with heart failure after 3 months of ASO. He was stable with oral treatment, therefore we performed the LMT reconstruction, before starting school, in terms of the risk of coronary ischemic event. We reconstructed the LMT ostium using an aortic flap and autologous pulmonary arterial patch. The postoperative computed tomography showed neither stenosis nor kinking at the repair site of LMT. He remains asymptomatic for over 6 months. We have reported that this method is effective to repair coronary artery anomalies (CAAs), since using an aortic flap. We could form a coronary artery floor, which is affixed to the aortic wall. This method allows us to change the coronary orifice position and the angle, so it is very useful method not for only CAAs, but also for coronary stenosis after ASO.

Tricuspid atresia 1c accompanying neonatal encephalopathy treated with pulmonary trunk banding and therapeutic hypothermia.

The influence of therapeutic hypothermia, known to improve neurodevelopmental outcomes in neonatal encephalopathy, remains unknown in newborns with severe congenital heart diseases. We report a neonate with tricuspid atresia type 1c suffering from moderate neonatal encephalopathy. A burst suppression pattern on amplitude-integrated electroencephalography recovered after inducing moderate therapeutic hypothermia, but exacerbated pulmonary overcirculation still persisted even after the rewarming. Since the medical treatment for pulmonary overcirculation had reached the limit, semi-urgent pulmonary trunk banding was performed on the 4th day of life. Postoperative brain magnetic resonance imaging showed no apparent brain injuries; the patient was discharged uneventfully. We share our perioperative management experience of a patient with tricuspid atresia type Ic who required therapeutic hypothermia for neonatal encephalopathy.

A modified nonsurgical treatment of keloids: Cocktail therapy.

BACKGROUND: The high recurrence rate after nonsurgical treatment of keloid is a major challenge for clinicians. Although there are many existing treatment options, how to optimize and upgrade the existing options and make a reasonable combination of utilization is our concern. The aim of this study is to provide a comprehensive non-surgical treatment for keloid-cocktail therapy. METHODS: According to the different changes of keloid with treatment, the treatment was divided into four stages, and different treatment schemes were adopted for each stage. The incidence of side effects of keloid at each stage and the effective rate and cure rate 16 months after the end of treatment were analyzed. RESULTS: All patients completed this study on time, and were followed up 16 months after the end of treatment, the treatment effective rate was 100%, and the cure rate was up to 92.8%. CONCLUSION: Cocktail therapy can achieve a higher cure rate of keloid, and is worthy of clinical promotion.

Nanomaterial Production from Metallic Vapor Bubble Collapse in Liquid Nitrogen.

Nanomaterials with unique structural and properties can be synthesized by rapid transition of the thermodynamic state. One promising method is through electrical explosion, which possesses ultrafast heating/quenching rates (dT/dt~109 K/s) of the exploding conductor. In this study, experiments were performed with fine metallic wire exploding in liquid nitrogen (liq N2, 77 K) under different applied voltages. For the first time in the literature, the physical image of the electrical explosion dynamics in liq N2 is depicted using electro-physical diagnostics and spatial-temporal-resolved photography. Specifically, the pulsation and collapse processes of the vapor bubble (explosion products) have been carefully observed and analyzed. As a comparison, an underwater electrical explosion was also performed. The experimental results suggest that the vapor bubble behavior in liq N2 differs from that in water, especially in the collapse phase, characterized by secondary small-scale bubbles in liq N2, but multiple bubble pulses in water; correspondingly, the products' characteristics are discrepant.

New pattern of individualized management of chronic diseases: focusing on inflammatory bowel diseases and looking to the future.

Non-infectious chronic diseases, especially inflammatory bowel diseases (IBDs), hypertension, and diabetes mellitus, are characterized by a prolonged and multisystemic course, and their incidence increases annually, usually causing serious economic burden and psychological stress for patients. Therefore, these diseases deserve scientific and consistent disease management. In addition, the lack of a comprehensive "early disease clues tracking-personalized treatment system-follow-up" model in hospitals also exacerbates this dilemma. Based on these facts, we propose an individualized prediction management system for IBDs based on chronic diseases, focusing on the established IBDs-related prediction models and summarizing their advantages and disadvantages. We call on researchers to pay attention to the integration of models with clinical practice and the continuous correction of models to achieve truly individualized medical treatment for chronic diseases, thus providing substantial value for the rapid diagnosis and adequate treatment of chronic diseases such as IBDs, which follow the "relapse-remission" disease model, and realizing long-term drug use and precise disease management for patients. The goal is to achieve a new level of chronic disease management by scientifically improving long-term medication, precise disease management, and individualized medical treatment, effectively prolonging the remission period and reducing morbidity and disability rates.

Nanofluidic Device for Detection of Lysine Methylpeptides and Sensing of Lysine Methylation.

Protein methylation is the smallest possible yet vitally important post-translational modification (PTM). This small and chemically inert addition in proteins makes the analysis of methylation more challenging, thus calling for an efficient tool for the sake of recognition and detection. Herein, we present a nanofluidic electric sensing device based on a functionalized nanochannel that was constructed by introducing monotriazole-containing p-sulfonatocalix[4]arene (TSC) into a single asymmetric polymeric nanochannel via click chemistry. The device can selectively detect lysine methylpeptides with subpicomole sensitivity, distinguish between different lysine methylation states, and monitor the lysine methylation process by methyltransferase at the peptide level in real time. The introduced TSC molecule, with its confined asymmetric configuration, presents the remarkable ability to selectively bind to lysine methylpeptides, which, coupled with the release of the complexed Cu ions, allows the device to transform the molecular-level recognition to the discernible change in ionic current of the nanofluidic electric device, thus enabling detection. This work could serve as a stepping stone to the development of a new methyltransferase assay and the chemical that specifically targets lysine methylation in PTM proteomics.

QM Calculations Revealed that Outer-Sphere Electron Transfer Boosted O-O Bond Cleavage in the Multiheme-Dependent Cytochrome bd Oxygen Reductase.

The cytochrome bd oxygen reductase catalyzes the four-electron reduction of dioxygen to two water molecules. The structure of this enzyme reveals three heme molecules in the active site, which differs from that of heme-copper cytochrome c oxidase. The quantum chemical cluster approach was used to uncover the reaction mechanism of this intriguing metalloenzyme. The calculations suggested that a proton-coupled electron transfer reduction occurs first to generate a ferrous heme b595. This is followed by the dioxygen binding at the heme d center coupled with an outer-sphere electron transfer from the ferrous heme b595 to the dioxygen moiety, affording a ferric ion superoxide intermediate. A second proton-coupled electron transfer produces a heme d ferric hydroperoxide, which undergoes efficient O-O bond cleavage facilitated by an outer-sphere electron transfer from the ferrous heme b595 to the O-O σ* orbital and an inner-sphere proton transfer from the heme d hydroxyl group to the leaving hydroxide. The synergistic benefits of the two types of hemes rationalize the highly efficient oxygen reduction repertoire for the multi-heme-dependent cytochrome bd oxygen reductase family.

Potential Protective Function of Adiponectin in Diabetic Retinopathy.

Adiponectin, one of the most ubiquitous adipokines found in the blood, plays a major role in glucolipid metabolism and energy metabolism and regulation. In recent years, a growing body of research indicates that adiponectin also plays a significant role in diabetic retinopathy. In the present review, we specifically address the protective effects of adiponectin on the development and progression of diabetic retinopathy through improvement in insulin resistance, alleviation of oxidative stress, limiting of inflammation, and prevention of vascular remodeling, with the aim to explore new potential approaches and targets for the prevention and treatment of diabetic retinopathy.

Identification of tagged glycans with a protein nanopore.

Structural complexity of glycans derived from the diversities in composition, linage, configuration, and branching considerably complicates structural analysis. Nanopore-based single-molecule sensing offers the potential to elucidate glycan structure and even sequence glycan. However, the small molecular size and low charge density of glycans have restricted direct nanopore detection of glycan. Here we show that glycan sensing can be achieved using a wild-type aerolysin nanopore by introducing a facile glycan derivatization strategy. The glycan molecule can induce impressive current blockages when moving through the nanopore after being connected with an aromatic group-containing tag (plus a carrier group for the neutral glycan). The obtained nanopore data permit the identification of glycan regio- and stereoisomers, glycans with variable monosaccharide numbers, and distinct branched glycans, either independently or with the use of machine learning methods. The presented nanopore sensing strategy for glycans paves the way towards nanopore glycan profiling and potentially sequencing.

Deciphering the Selectivity of the Electrochemical CO2 Reduction to CO by a Cobalt Porphyrin Catalyst in Neutral Aqueous Solution: Insights from DFT Calculations.

Density functional theory (DFT) calculations were conducted to investigate the cobalt porphyrin-catalyzed electro-reduction of CO2 to CO in an aqueous solution. The results suggest that CoII -porphyrin (CoII -L) undertakes a ligand-based reduction to generate the active species CoII -L⋅- , where the CoII center antiferromagnetically interacts with the ligand radical anion. CoII -L⋅- then performs a nucleophilic attack on CO2 , followed by protonation and a reduction to give CoII -L-COOH. An intermolecular proton transfer leads to the heterolytic cleavage of the C-O bond, producing intermediate CoII -L-CO. Subsequently, CO is released from CoII -L-CO, and CoII -L is regenerated to catalyze the next cycle. The rate-determining step of this CO2 RR is the nucleophilic attack on CO2 by CoII -L⋅- , with a total barrier of 20.7 kcal mol-1 . The competing hydrogen evolution reaction is associated with a higher total barrier. A computational investigation regarding the substituent effects of the catalyst indicates that the CoPor-R3 complex is likely to display the highest activity and selectivity as a molecular catalyst.

Profile of biological characterizations and clinical application of corneal stem/progenitor cells.

Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.

[Midterm Outcomes of Pulmonary Valve Leaflet Augmentation using Fresh Autologous Pericardium for Transannular Patch Repair of Tetralogy of Fallot].

BACKGROUND: Although valve sparing (VS) for patients with smaller pulmonary valves has been increasing, transannular patch repair( TAP) accounts for more than half of the total tetralogy of Fallot corrections worldwide. We use fresh autologous pericardial patches to perform a modified TAP procedure with pulmonary valve leaflet augmentation as proposed by Sung et al. We aimed to explore the early and midterm outcomes of this procedure. METHODS: We retrospectively reviewed 37 patients( group TAP:12;group VS:25) who underwent total tetralogy of Fallot corrections from April 2018 to December 2021. RESULTS: No midterm mortality was observed at a median observation period of 20.4 months in both groups. The midterm rates of freedom from moderate or more pulmonary regurgitation( PR) were 64.2 % and 21.4% in group TAP and 100% and 100% in group VS at 1 and 3 years, respectively( p<0.001). The midterm rates of freedom from pulmonary stenosis reintervention were 100% and 100% in group TAP and 96% and 96% in group VS at 1 and 3 years, respectively( p=0.51). CONCLUSIONS: TAP showed acceptable midterm survival and reintervention rate. Longer follow-up is essential considering the significantly higher PR in the postoperative period in group TAP.

Recent Advances in the Modification and Characterization of Solid-State Nanopores.

Nanopores, due to their advantages of being modifiable, controllability and sensitivity, have made a splash in recent years in the fields of biomolecular sequencing, small molecule detection, salt differential power generation, and biomimetic ion channels. In these applications, the role of chemical or biological modification is indispensable. Compared with small molecules, the modification of polymers is more difficult and the methods are more diverse. Choosing an appropriate modification method directly determines the success or failure of a research project; therefore, it is necessary to summarize polymer modification methods toward nanopores. In addition, it is also important to provide clear and convincing evidence that the nanopore modification is successful, the corresponding characterization methods are also indispensable. Therefore, this review will summarize the methods of polymer modification of nanopores and efficient characterization methods. We hope that this review will provide some reference value for like-minded researchers.