Upregulating miR-181b promotes ferroptosis in osteoarthritic chondrocytes by inhibiting SLC7A11.

BACKGROUND: Osteoarthritis (OA) is a common disease with a complex pathology. This study aimed to investigate the correlation between the aberrant upregulation of miR-181b and ferroptosis in chondrocytes during the progression of OA. METHODS: An OA cell model was constructed with erastin. Ferrostatin-1 (Fer), bioinformatics, and dual-luciferase activity reports were used to investigate the effect of miR-181b on OA. Finally, a rat model of OA was induced by monosodium iodoacetate to verify that miR-181b inhibits SLC7A11 gene expression and increases ferroptosis. RESULTS: The results showed that Fer could effectively reverse the erastin-induced inhibition of human chondrocyte viability, increase the level of collagenous proteins in human chondrocytes, and inhibit oxidative stress and ferroptosis. MiR-181b is abnormally elevated in OA cell models. Transfection of a miR-181b inhibitor could increase the expression levels of the ferroptosis-related proteins solute carrier family 7 members 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby inhibiting the occurrence of ferroptosis in chondrocytes. In addition, hsa-miR-181b-5p and SLC7A11 have a targeted regulatory effect. Transfection of SLC7A11 siRNA effectively abrogated the increase in chondrocyte viability induced by the miR-181 inhibitor and increased ferroptosis. Finally, miR-181b was shown to exacerbate OA disease progression by inhibiting SLC7A11 gene expression and increasing ferroptosis in a rat OA model. CONCLUSIONS: Elevating miR-181b may mediate chondrocyte ferroptosis by targeting SLC7A11 in OA.

Presence and Absence of Barren Plateaus in Tensor-Network Based Machine Learning.

Tensor networks are efficient representations of high-dimensional tensors with widespread applications in quantum many-body physics. Recently, they have been adapted to the field of machine learning, giving rise to an emergent research frontier that has attracted considerable attention. Here, we study the trainability of tensor-network based machine learning models by exploring the landscapes of different loss functions, with a focus on the matrix product states (also called tensor trains) architecture. In particular, we rigorously prove that barren plateaus (i.e., exponentially vanishing gradients) prevail in the training process of the machine learning algorithms with global loss functions. Whereas, for local loss functions the gradients with respect to variational parameters near the local observables do not vanish as the system size increases. Therefore, the barren plateaus are absent in this case and the corresponding models could be efficiently trainable. Our results reveal a crucial aspect of tensor-network based machine learning in a rigorous fashion, which provide a valuable guide for both practical applications and theoretical studies in the future.

Unsupervised Learning of Non-Hermitian Topological Phases.

Non-Hermitian topological phases bear a number of exotic properties, such as the non-Hermitian skin effect and the breakdown of conventional bulk-boundary correspondence. In this Letter, we introduce an unsupervised machine learning approach to classify non-Hermitian topological phases based on diffusion maps, which are widely used in manifold learning. We find that the non-Hermitian skin effect will pose a notable obstacle, rendering the straightforward extension of unsupervised learning approaches to topological phases for Hermitian systems ineffective in clustering non-Hermitian topological phases. Through theoretical analysis and numerical simulations of two prototypical models, we show that this difficulty can be circumvented by choosing the "on-site" elements of the projective matrix as the input data. Our results provide a valuable guidance for future studies on learning non-Hermitian topological phases in an unsupervised fashion, both in theory and experiment.

MIB1 mutations reduce Notch signaling activation and contribute to congenital heart disease.

Congenital heart disease (CHD) is one of the most common birth defects in humans, but its genetic etiology remains largely unknown despite decades of research. The Notch signaling pathway plays critical roles in embryonic cardiogenesis. Mind bomb 1 (Mib1) is a vital protein that activates the Notch signaling pathway through promoting ubiquitination, endocytosis and subsequent activation of Notch ligands. Previous studies show that Mib1 knockout in mice completely abolishes Notch signaling, leading to cardiac deformity. However, the function of MIB1 and its potential disease-causing mutations are poorly studied in human CHD. In this research, we identified four novel non-synonymous heterozygous rare mutations of MIB1 from 417 Han Chinese CHD patients. The following biochemical analyses revealed that mutations p.T312K fs*55 and p.W271G significantly deplete MIB1's function, resulting in a lower level of JAGGED1 (JAG1) ubiquitination and Notch signaling induction. Our results suggest that pathologic variants in MIB1 may contribute to CHD occurrence, shedding new light on the genetic mechanism of CHD in the context of the Notch signaling pathway.

Declining Pulmonary Function in Populations with Long-term Exposure to Polycyclic Aromatic Hydrocarbons-Enriched PM2.5.

This study assesses the effects of long-term exposure to ambient air pollutants on inflammatory response and lung function. We selected 390 male coke oven workers with exposure to polycyclic aromatic hydrocarbons (PAHs) and fine particulate matter (PM2.5) and 115 control workers. The average duration in the exposed group was 9.10 years. The total amount of PAHs was more enriched in PM2.5 which collected from the coke oven workshops compared with the control areas. Correspondingly, the internal PAHs exposure indicated by urinary 1-hydroxypyrene (1-OHP) in the exposure group increased 25.7-fold compared to that of the control group. Moreover, the increasing level of urinary 1-OHP was associated with the decrease of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC). In non-current smokers of exposure group, inverse correlation of 1-OHP with FEV1/FVC was also found. Particularly, an exposure duration-dependent decline in FEV1/FVC and mean forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%) indicated that small airways were functionally obstructed. Furthermore, the increasing serum high-sensitivity C-reactive protein (hs-CRP) was correlated with the decline in pulmonary function in all subjects. These findings provide a clue that long-term exposure to PAHs-enriched PM2.5 impairs pulmonary function in occupational population.

Asymmetric vanadium flow batteries: long lifespan via an anolyte overhang strategy.

Fast capacity decay is a serious problem in vanadium flow batteries (VFBs). How to eliminate or slow down capacity fading has become a critical issue for the practical application of VFBs. Herein, the concept of an asymmetric vanadium flow battery (aVFB) is introduced, in which the asymmetric design of a catholyte and an anolyte is used to suppress the capacity decay of the VFB. Based on the comprehensive analysis of the capacity decay and electrolyte imbalance process of the traditional symmetric VFB, it was found that the capacity fading is mainly owing to the loss of the anolyte in the long-term cycling test. Therefore, this work attempts to use excess anolyte (i.e. 10%, 20% and 30%) to mitigate the capacity decay during the long-term operation of the VFB. To gain deeper insights into the capacity retention mechanism of these novel anolyte overhang aVFBs, long-term cycle performance of the corresponding symmetric overhang VFBs and catholyte overhang aVFBs is investigated for comparison. The optimal excess ratio of anolyte and how to add the excess anolyte are also suggested for future study.

In situ study of oxidation states of platinum nanoparticles on a polymer electrolyte fuel cell electrode by near ambient pressure hard X-ray photoelectron spectroscopy.

We performed in situ hard X-ray photoelectron spectroscopy (HAXPES) measurements of the electronic states of platinum nanoparticles on the cathode electrocatalyst of a polymer electrolyte fuel cell (PEFC) using a near ambient pressure (NAP) HAXPES instrument having an 8 keV excitation source. We successfully observed in situ NAP-HAXPES spectra of the Pt/C cathode catalysts of PEFCs under working conditions involving water, not only for the Pt 3d states with large photoionization cross-sections in the hard X-ray regime but also for the Pt 4f states and the valence band with small photoionization cross-sections. Thus, this setup allowed in situ observation of a variety of hard PEFC systems under operating conditions. The Pt 4f spectra of the Pt/C electrocatalysts in PEFCs clearly showed peaks originating from oxidized Pt(ii) at 1.4 V, which unambiguously shows that Pt(iv) species do not exist on the Pt nanoparticles even at such large positive voltages. The water oxidation reaction might take place at that potential (the standard potential of 1.23 V versus a standard hydrogen electrode) but such a reaction should not lead to a buildup of detectable Pt(iv) species. The voltage-dependent NAP-HAXPES Pt 3d spectra revealed different behaviors with increasing voltage (0.6 → 1.0 V) compared with decreasing voltage (1.0 → 0.6 V), showing a clear hysteresis. Moreover, quantitative peak-fitting analysis showed that the fraction of non-metallic Pt species matched the ratio of the surface to total Pt atoms in the nanoparticles, which suggests that Pt oxidation only takes place at the surface of the Pt nanoparticles on the PEFC cathode, and the inner Pt atoms do not participate in the reaction. In the valence band spectra, the density of electronic states near the Fermi edge reduces with decreasing particle size, indicating an increase in the electrocatalytic activity. Additionally, a change in the valence band structure due to the oxidation of platinum atoms was also observed at large positive voltages. The developed apparatus is a valuable in situ tool for the investigation of the electronic states of PEFC electrocatalysts under working conditions.

Non-contact electric potential measurements of electrode components in an operating polymer electrolyte fuel cell by near ambient pressure XPS.

Photoelectron spectroscopy has the advantage of providing electric potentials by non-contact measurements based on the kinetic energy shift in component potential. We performed operando hard X-ray photoelectron spectroscopy (HAXPES) measurements with an 8 keV excitation source to measure the shift in electron kinetic energies as a function of the voltages of all the components at the anode and cathode electrodes of a polymer electrolyte fuel cell (PEFC). At the cathode electrode, when we increase the voltage between the cathode and anode from 0.2 to 1.2 V, the O 1s and F 1s peaks shift to a lower binding energy and the magnitude of the energy shift is equal to the voltage. The Pt 3d and C 1s peaks do not shift with the voltage since platinum nanoparticles and carbon supports at the cathode electrode have ground contact. In contrast to the cathode electrode, the peak shifts of all the components at the anode electrode show the same amount of shift as the voltages. It is clear that the change in the potential difference occurs only in an electrical double layer at the interface between the cathode electrode (Pt/C) and the electrolyte (Nafion and water), and that the anode electrode is in equilibrium as a pseudo-hydrogen electrode. Moreover, the electric potential variation of the cathode electrode in a PEFC under a power generation condition was also directly detected by operando HAXPES.

[Research on Application of Fourier Transform Infrared Spectrometry in the Diagnosis of Lymph Node Metastasis in Gastric Cancer].

To explore the feasibility of quick intraoperative in situ and noninvasive diagnosis of lymph node metastasis in gastric cancer by Fourier transform infrared (FTIR) spectrometry. FTIR spectra of surgically removed fresh lymph nodes were measured by FTIR via probe of attenuated total reflection (ATR). For each spectrum, 13 bands were indentified and assigned between 3 000 and 1 000 cm(-1). Peaks in the spectra were measured and relative intensity ratios were calculated and compared between the spectra of Metastatic lymph nodes (MLN) and Non-metastatic lymph nodes (NMLN). Standard statistic analysis was performed. 720 lymph nodes were measured in 38 gastric cancer patients. Results show that there were significant differences between the FTIR of 540 MLN and 180 NMLN. (1) For the band related to nucleic acid: The ratios of I1240/I1460 (p = 0.015) and I1080/I1460 (p = 0.034) increased in MLN, which shows that the relative quantity of nucleic acid was more in MLN than that in NMLN. (2) For the bands related to protein: The ratios of I1640 /I1460 (p = 0.001) and I146/I1460 (p = 0.027) increased in MLN, which shows that the relative quantity of protein was more in MLN. (3) For the bands related to lipid: The ratio of I2855/I460 and I1740/I1460 decreased in MLN FTIR spectrum, indicating the lower relative quantity of lipid in MLN. (4) For the bands related to carbohydrate: The ratio of I1160/I1460 (p = 0.023) decreased in MLN FTIR spectrum, indicating the lower relative quantity of carbohydrate in MLN. The results demonstrate that the FTIR spectroscopy technique maybe develop into a promising method for in situ and quick intraoperative differential diagnosis of lymph node metastasis in gastric cancer.

miR-10a and miR-10b target the 3'-untranslated region of TBX5 to repress its expression.

As a well-known transcription factor, TBX5 is involved in embryonic cardiac development. Although TBX5 functions in a dose-dependent manner, the posttranscriptional regulation of human TBX5 is poorly understood. Thus, this study aimed to identify microRNAs that modulate TBX5 expression. Luciferase assays were used to screen miRNAs predicted to modulate TBX5 expression. Using quantitative reverse transcriptase-polymerase chain reaction and Western blot analysis, the authors found that miR-10a and miR-10b significantly repressed TBX5 expression and decreased TBX5 protein levels by targeting the TBX5 3'-untranslated region. In addition, miR-10a and miR-10b expression levels were respectively 2.77 and 3.51 times higher in the heart tissues of congenital heart disease patients than in healthy control subjects, suggesting that they are potential diagnostic biomarkers. In conclusion, the study results indicate that miR-10a and miR-10b inhibit TBX5 expression at the level of translation. Higher levels of miR-10a and miR-10b expression are associated with a higher risk of congenital heart defects.

[Research of progress of mitochondria in the pathogenesis of sepsis].

Sepsis is an organ dysfunction caused by dysregulation of the body's response to infection, with high morbidity and mortality. The pathogenesis of sepsis is still unclear, and there are no specific treatment drugs. As a cell energy supply unit, the dynamic changes of mitochondria are closely related to various diseases. Studies have shown that structure and function of mitochondria are changed in different organs during sepsis. The energy shortage, oxidative stress change, imbalance of fusion and fission, autophagy reduce, biological functions of mitochondria play important roles in sepsis progress, which can provide a research target for the treatment of sepsis.

EoE behaves as a unique Th2 disease: a narrative review.

Background and Objective: To highlight and interpret two significant differences between eosinophilic esophagitis (EoE), a type 2 helper cell (Th2) disease, and three other representative Th2 diseases. EoE, asthma, atopic dermatitis (AD), chronic rhinosinusitis (CRS) and other Th2 diseases employ epithelial alarmins to recognize triggers, share a prototypical inflammatory cascade, and respond to glucocorticoids. However, EoE also has several distinguishing characteristics which may be explained by a distinct pathophysiologic mechanism. Methods: The following report consist of four related narrative reviews which combine comprehensive PubMed and Google searches. Two reviews were performed to identify and contrast all eligible studies describing serologic markers in EoE compared to asthma, AD, and CRS. Two additional reviews then compare the responses to parenteral biological therapies in EoE and in the same representative Th2 diseases. Key Content and Findings: Comprehensive literature searches definitively differentiate the absence of serologic markers in EoE compared to their identification in the other representative Th2 diseases. Similarly, a summary of therapeutic trials demonstrates that while EoE is unable to clinically respond to a variety of parenteral biological therapies, asthma, AD and CRS are very effectively treated with this same approach. A novel pathophysiology for EoE is proposed, and the emerging literature that support its existence is summarized. Conclusions: The fundamental properties described in this narrative regarding serologic signaling and response to parenteral therapy in EoE could be explained if EoE employs a unique application of the Th2 pathway. One potential mechanism consistent with these observations is that EoE employs exclusively esophageal mucosal constituents to initiate and generate the prototypical Th2 cascade and the fibrostenotic changes that follow.

Transcatheter Treatment of Native Coarctation of the Aorta in a Child Using a Balloon-Expandable Endoprosthesis.

A 7-year-old child with native coarctation of the aorta was treated by transcatheter therapy using a 29-mm balloon-expandable stent. The procedure was successful and free of complications, and the patient was discharged home the same day. This stent has several features making it uniquely advantageous for treating this condition. (Level of Difficulty: Advanced.).

ED90 of epidural esketamine with 0.075% ropivacaine for labor analgesia in nulliparous parturients: a prospective, randomized and dose-finding study.

Background: Because it has been reported that racemic ketamine had a local anesthetic-sparing effect when used for epidural analgesia this would suggest the likelihood of a potential advantage (less pruritus) over opioid drugs. Esketamine has greater analgesic efficacy than racemic ketamine, but the optimum dosage regimen for epidural use is undetermined. The aim of this study was to determine the ED90 of epidural esketamine when coadministered with 0.075% ropivacaine for labor analgesia. Methods: A total of 65 laboring nulliparous patients were enrolled in this study from 16 March 2022 to 15 October 2022. The patients were randomly assigned to receive 0, 0.25, 0.5, 0.75 or 1.0 mg/mL esketamine with 0.075% ropivacaine epidurally. An effective response to the epidural loading dose was defined as numerical rating scale pain score ≤3 at 30 min after the end of the epidural loading dose (10 mL of the ropivacaine 0.075% solution with the added esketamine). The ED90 of epidural esketamine coadministered with 0.075% ropivacaine with 95% confidence intervals for labor analgesia was determined using probit regression. Secondary outcomes and side effects were recorded. Results: The estimated value of ED90 with 95% CIs for epidural esketamine with 0.075% ropivacaine was 0.983 (0.704-2.468) mg/mL. The characteristics of sensory and motor block, consumption of ropivacaine per hour, duration of first or second stage, Apgar scores did not differ among the five groups. The incidence of mild dizziness in Group esketamine 1.0 mg/mL was significantly higher than that in other groups (p < 0.05). No statistical differences were found in other side effects among groups. Conclusion: The ED90 value of epidural esketamine coadministered with 0.075% ropivacaine for labor analgesia in nulliparous parturients was about 1.0 mg/mL. Furthermore, our results suggested that epidural esketamine would cause dose-dependent mild dizziness especially at doses up to 1.0 mg/mL. As a single epidural additive, esketamine may not be suitable for labor analgesia. Future studies may investigate the appropriate dosage of esketamine at slightly higher concentrations of local anesthetics or larger initial volume of analgesia, or explore other potential advantages of esketamine. Clinical Trial Registration: (https://www.chictr.org.cn/bin/project/edit?pid=159764), identifier (ChiCTR2200057662).

[Post-transcriptional protein modification of Gata4].

Gata4 is an important transcription factor in heart development. Gata4 post-transcriptional protein modification regulates transcriptional activity and DNA binding, which in turn affects expression of downstream genes and transcription factors, differentiation of embryonic stem cells and cardiogenesis. This article summarizes the effect of post-transcriptional protein modification on transcriptional activity of Gata4 and the relationship between this effect and congenital heart disease. It was shown that acetylation, phosphorylation and SUMOylation upregulate transcriptional activity, DNA binding, downstream gene expression and embryonic stem cell differentiation. On the other hand, methylation and deacetylation downregulate Gata4 transcriptional activity. Post-transcriptional protein modification of Gata4 is very important in clinical research on congenital and other heart diseases.

Effect of Mineral Admixtures on the Performance of Ceramsite Shotcrete for High Geothermal Underground Engineering.

Ceramsite concrete is used in lining structures of underground engineering in the geothermal environment. This study, by means of mixing fly ash and silica fume, aims at diminishing the adverse effects on concrete performance caused by elevated temperature in high geothermal underground engineering. Under simulated geothermal conditions (20, 40, and 60 °C, RH ≥ 90%), it was first proposed that 15 and 5 wt % cement replacements by fly ash and silica fume, respectively, were most optimal. Then, the effect of mineral admixtures on ceramsite shotcrete performance was investigated. The results show that the mixing of fly ash and silica fume could improve ceramsite shotcrete adaptability in elevated curing temperature. Particularly for silica fume, at 40 °C curing temperature, the 28-day compressive strength and splitting tensile strength increased by 12.6 and 50.9%, respectively. The improvement effect of silica fume on permeability resistance and resistance to chloride ion permeability was higher than that of fly ash. Nevertheless, the mixing of fly ash was more effective than silica fume for reducing thermal conductivity.

Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease.

The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc. Deleterious mutations in GLI genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in GLI1-3 genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human GLI1-3 genes were identified. Functional analyses showed that GLI1 c.820G> T (p.G274C) is a gain-of-function mutation, while GLI1 c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in GLI1 gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.

Effect of Highland Barley on Rheological Properties, Textural Properties and Starch Digestibility of Chinese Steamed Bread.

Highland barley has a different composition and structure to other crops. It has higher contents of total polyphenol (TPC), total flavonoid (TFC) and ß-glucan, which can be supplemented to improve the nutrition of wheat-flour-based food. In this study, the flours of three different grain-colored highland barley varieties Beiqing 6 (BQ), Dulihuang (DLH), and Heilaoya (HLY), were added to Jimai60 (JM, a wheat variety with medium gluten) wheat flour at different substitution levels to investigate their effects on the unextractable polymeric protein (UPP) content, micro-structure, rheological properties and mixing properties of dough, and the color, texture, flavor, and in vitro digestion of Chinese steam bread (CSB). The results showed that the moderate substitution of highland barley (20%) increased the UPP%, optimized the micro-structure of gluten, and improved its rheological properties by increasing dough viscoelasticity. The CSBs made from the composite flours exhibited a similar specific volume, cohesiveness, springiness and resilience to wheat CSB, while the firmness of composite CSBs (particularly JM-HLY-20) was delayed during storage. Importantly, the addition of highland barley increased the contents of TPC, TFC and ß-glucan, but decreased the in vitro starch digestibility of CSBs. A sensory evaluation showed that JM-HLY CSB was the most preferable. Taken together, highland barley can be used as a fine supplement to food products, with health-promoting properties.

Pediatric Eosinophilic Esophagitis: Searching for Serologic Markers.

OBJECTIVE: Eosinophilic esophagitis (EoE) is a Th2 disease that presently is diagnosed and followed by clinical symptoms in the presence of endoscopic biopsies documenting elevated esophageal eosinophilia. To simplify clinical care, multiple studies have attempted to identify a disease specific serologic marker. None have been successful. The goal of this study was to employ custom designed Luminex multiplex bead assays to identify a reliable serologic marker for EoE. METHODS: Luminex assays were employed to measure serum levels of 11 analytes associated with EoE (IL-5, lL13, periostin, eotaxin-3, thymic stromal lymphopoietin, and immunoglobulins) in a cohort of pediatric patients consisting of active EoE (n=30), EoE in remission (n=13), and controls (n=34). RESULTS: No analyte was found to be elevated or depressed in active EoE compared to the other groups. Additionally, among the cohort with active EoE, none of the 11 analytes correlated with peak esophageal eosinophilia, endoscopic features of EoE quantitatively defined by an EoE validated endoscopic reference score (EREFS), or esophageal thickness as determined by endosonography. CONCLUSION: This is the largest prospective survey of heterogeneous markers studied in a consecutive cohort to determine whether they could diagnose or follow EoE. Although none were identified in this cohort, Luminex provides a rapid, economical tool to simultaneously screen multiple sera for proteins that are increased or decreased in disease states.

Interaction of B-type starch with gluten skeleton improves wheat dough mixing properties by stabilizing gluten micro-structure.

Some recent studies have revealed individual and the combined interactions of gluten and starch affecting dough mixing properties. However, the combined influence of high-molecular-weight glutenin subunits (HMW-GS) and starch on dough mixing and rheological properties requires elucidation. Thus four recombinant inbred lines, SS 1, SS 2, ZZ 1 and ZZ 2, were selected based on their HMW-GSs compositions. Compared to ZZ 1 and ZZ 2, both SS 1 and SS 2 carried superior HMW-GS alleles, and exhibited extended dough development and stability time, indicating their significant dough mixing characteristics. The gluten skeleton of the wheat lines SS 2 and ZZ 2 with higher B-type starch proportions exhibited fewer breakages along with the rise of dough temperature during mixing. Higher content of B-type starch strengthens interaction between starch and gluten skeleton at the dough heating stage, suggesting a specific range of B-type starch proportion can improve dough mixing characteristics.