Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex.

BACKGROUND AND AIMS: Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis. APPROACH AND RESULTS: Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/ß-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays. The pharmacological relevance of molecular discoveries was intensified in primary cultures, rodent models, and human samples. HSC glycolysis was enhanced by Wnt3a but reduced by ß-catenin inhibitor or small interfering RNA (siRNA). Wnt3a-induced rapid transactivation and high expression of LDH-A dependent on TCF4. Wnt/ß-catenin signaling also stimulated LDH-A nuclear translocation through importin ß2 interplay with a noncanonical nuclear location signal of LDH-A. Mechanically, LDH-A bound to HIF-1α and enhanced its stability by obstructing hydroxylation-mediated proteasome degradation, leading to increased transactivation of glycolytic genes. The Gly28 residue of LDH-A was identified to be responsible for the formation of the LDH-A/HIF-1α transcription complex and stabilization of HIF-1α. Furthermore, LDH-A-mediated glycolysis was required for HSC activation in the presence of Wnt3a. Results in vivo showed that HSC activation and liver fibrosis were alleviated by HSC-specific knockdown of LDH-A in mice. ß-catenin inhibitor XAV-939 mitigated HSC activation and liver fibrosis, which were abrogated by HSC-specific LDH-A overexpression in mice with fibrosis. CONCLUSIONS: Inhibition of HSC glycolysis by targeting Wnt/ß-catenin signaling and LDH-A had therapeutic promise for liver fibrosis.

Solid-State Nanopore/Nanochannel Sensors with Enhanced Selectivity through Pore-in Modification.

Nanopore sensing technology, as an emerging analytical method, has the advantages of simple operation, fast output, and label-free and has been widely used in fields such as protein analysis, gene sequencing, and biomarker detection. Inspired by biological ion channels, scientists have prepared various artificial solid-state nanopores/nanochannels. Biological ion channels have extremely high ion transport selectivity, while solid-state nanopores/nanochannels have poor selectivity. The selectivity of solid-state nanopores and nanochannels can be enhanced by modifying channel charge, varying pore size, incorporating specific chemical functionality, and adjusting operating (or solution) conditions. This Perspective highlights pore-in modification strategies for enhancing the selectivity of solid-state nanopore/nanochannel sensors by summarizing the articles published in the last 10 years. The future development prospects and challenges of pore-in modification in solid-state nanopore and nanochannel sensors are discussed. This Perspective helps readers better understand nanopore sensing technology, especially the importance of detection selectivity. We believe that solid-state nanopore/nanochannel sensors will soon enter our homes after various challenges.

Clinical study on improving the function of female bladder in controlling urine by acupuncture Zhibian (BL54) under ultrasound guidance.

OBJECTIVE: To observe the effect of acupuncture Zhibian (BL54) on the function of the bladder in controlling urine in women under ultrasound. METHOD: 74 healthy subjects were randomly divided into deep acupuncture group of 37 cases and shallow acupuncture group of 37 cases. Under the guidance of ultrasound, the two groups of subjects were acupunctured at bilateral BL54. The deep acupuncture group was acupunctured to the pudendal nerve, and the shallow acupuncture group was acupunctured to the superficial fascia. Ultrasound was used to observe the peak systolic velocity (PSV), time average maximum velocity (TAMX), end diastolic velocity (EDV), pulsation index (PI), resistance index (RI) of the pudendal arteries, and bladder volume of two groups of subjects before and after acupuncture. The anatomical hierarchical structure of bilateral BL54 and score of Chinese version of the Massachusetts General Hospital Acupuncture Sensation Scale (C-MASS) of all subjects was measured. RESULT: After acupuncture, the PSV, TMAX of the pudendal artery, bladder volume, and the Score of C-MASS Scale in the deep acupuncture group were higher than in the shallow acupuncture group (P < 0.05). The RI of the pudendal arteries in the shallow acupuncture group decreased compared to before acupuncture (P < 0.05). CONCLUSION: Acupuncture at the BL54 can increase the blood flow velocity of the pudendal artery, improve the function of the bladder in controlling urine in women, and different depths of acupuncture will have different therapeutic effects.

Efficacy of Warm Acupuncture Therapy Combined with Kegel Exercise on Postpartum Pelvic Floor Dysfunction in Women.

INTRODUCTION AND HYPOTHESIS: The objective was to observe the clinical efficacy of warm acupuncture combined with Kegel exercise in treating postpartum pelvic floor dysfunction in women. METHODS: A total of 70 primiparous women with postpartum pelvic floor muscle (PFM) injury were randomly divided into a combination group (n = 35, receiving warm acupuncture at Zhibian (BL54) acupoint and Kegel exercise) and a sham control group (n = 35, receiving sham warm acupuncture and Kegel exercise). Both groups were treated three times a week for 4 consecutive weeks. The recovery of PFM strength and changes in Urethral Rotation Angle (URA), Bladder Neck Descent (BND), and Retrovesical Angle (RVA) in pelvic floor ultrasound reports, the scores of pelvic floor dysfunction-related questionnaires, and the efficacy of urinary incontinence treatment of the two groups were compared before and after treatment. RESULTS: After treatment, the recovery rates of type I and II PFM strength, pelvic floor ultrasound parameters, pelvic floor dysfunction-related scale scores, and urinary incontinence treatment efficacy in the combination group were significantly better than those in the sham control group (p < 0.05). CONCLUSION: Warm acupuncture combined with Kegel exercise can significantly improve PFM strength and promote the recovery of postpartum pelvic floor function in women.

Prognosticating Prosthetic Ambulation Ability in People With Lower Limb Amputation in Early Post-Operative Phase.

OBJECTIVE: To formulate a prognostication model in the early post-operation phase of lower limb amputation to predict patient's ability to ambulate with a prosthesis post rehabilitation. DESIGN: Retrospective cohort study, using data collected from electronic medical records. Predictive factors and prosthetic ambulation outcomes post rehabilitation were used to develop prognostic models via machine learning techniques. SETTING: Regional hospital's ambulatory rehabilitation clinic. PARTICIPANTS: Patients with major lower limb amputation (N=329). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcome of prosthetic ambulation ability post rehabilitation collected was categorized in 3 groups: non-ambulant with prosthesis, homebound ambulant with prosthesis (AP), and community AP. RESULTS: In a 2-class model of non-ambulant and AP (homebound and community), the model with highest accuracy of prediction included ethnicity, total Functional Comorbidity Index (FCI), level of amputation, being community ambulant prior to amputation, and age. The f1-score and area under receiver operator curve (AUROC) of the model is 0.78 and 0.82. In a 3-class model consisting of all 3 groups of outcomes, the model with highest accuracy of prediction required 10 factors. The additional factors from the 2-class model include presence of caregiver, history of congestive heart failure, diabetes, visual impairment, and stroke. The 3-class model has a moderate accuracy with a f1-score and AUROC of 0.60 and 0.79. CONCLUSION: The 2-class prognostication model has a high accuracy which can be used early post-amputation to predict if patient would be ambulant with a prosthesis post rehabilitation. The 3-class prognostication model has moderate accuracy and is able to further differentiate the walking ability to either homebound or community ambulation with a prosthesis, which can assist in prosthetic prescription and setting realistic rehabilitation goals.

Effect of liver transplants with retrograde reperfusion on early postoperative recovery of liver function and its risk factors.

BACKGROUND: The purpose of this study was to investigate effect of liver Transplants (LT) with retrograde reperfusion on early postoperative recovery of liver function and its risk factors. METHODS: We conducted a retrospective analysis of clinical data from 136 liver transplantation (LT) patients at the 900th Hospital of the Chinese People's Liberation Army Joint Support Army, covering the period from January 2015 to January 2021. All participants provided informed consent, adhering to medical ethics guidelines. Patients were stratified into two groups based on the liver perfusion technique used: retrograde reperfusion (RTR, n = 108) and initial portal reperfusion (IPR, n = 28). Our study focused on a subset of 23 patients from each group to compare postoperative liver function recovery. The final analysis included 86 RTR and 28 IPR cases after excluding 8 RTR patients who underwent initial hepatic artery reperfusion and 14 who received simultaneous hepatic artery and portal vein reperfusion. Further subdivision within the RTR group identified 19 patients with early hepatic allograft dysfunction (EAD) and 67 without, allowing for an assessment of the influence of preoperative and intraoperative parameters, as well as perfusion methods, on EAD incidence post-LT. RESULTS: Alanine aminotransferase (ALT) was 329 (211 ~ 548) and 176 (98 ~ 282) U/L on the 3rd and 7th day after RTR, respectively, which was significantly lower than 451 (288 ~ 918) and 251 (147 ~ 430) U/L in the IPR group (Z =-1.979, -2.299, P = 0.048, 0.021). Aspartate aminotransferase (AST) on postoperative days 3, 5, and 7 was 252 (193, 522), 105 (79, 163), and 93 (41, 135) U/L in the RTR group, respectively; it was also significantly lower than 328 (251, 724), 179 (129, 306), and 150 (91, 200)U/L in the IPR group (Z=-2.212, -3.221, -2.979; P = 0.027, 0.001, 0.003). Logistic regression analysis showed that MELD score was an independent risk factor for EAD after LT. CONCLUSION: RTR LT is more favorable for patients' early postoperative liver function recovery. For patients undergoing LT for RTR, preoperative MELD score was an independent risk factor for their postoperative development of EAD.

Intake of tobacco nitrosamines of smokers in various provinces of China and their cancer risk: A meta-analysis.

Nitrosamines are a class of carcinogens which have been detected widely in food, water, some pharmaceuticals as well as tobacco. The objectives of this paper include reviewing the basic information on tobacco consumption and nitrosamine contents, and assessing the health risks of tobacco nitrosamines exposure to Chinese smokers. We searched the publications in English from "Web of Science" and those in Chinese from the "China National Knowledge Infrastructure" in 2022 and collected 151 literatures with valid information. The content of main nitrosamines in tobacco, including 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosonornicotine (NNN), N-nitrosoanatabine (NAT), N-nitrosoanabasine (NAB), total tobacco-specific nitrosamines (TSNA), and N-nitrosodimethylamine (NDMA) were summarized. The information of daily tobacco consumption of smokers in 30 provinces of China was also collected. Then, the intakes of NNN, NNK, NAT, NAB, TSNAs, and NDMA via tobacco smoke were estimated as 1534 ng/day, 591 ng/day, 685 ng/day, 81 ng/day, 2543 ng/day, and 484 ng/day by adult smokers in 30 provinces, respectively. The cancer risk (CR) values for NNN and NNK inhalation intake were further calculated as 1.44 × 10-5 and 1.95 × 10-4. The CR value for NDMA intake via tobacco smoke (inhalation: 1.66 × 10-4) indicates that NDMA is similarly dangerous in tobacco smoke when compared with the TSNAs. In China, the CR values caused by average nitrosamines intake via various exposures and their order can be estimated as the following: smoke (3.75 × 10-4) > food (1.74 × 10-4) > drinking water (1.38 × 10-5). Smokers in China averagely suffer 200% of extra cancer risk caused by nitrosamines in tobacco when compared with non-smokers.

A Single Set of Well-Designed Aptamer Probes for Reliable On-site Qualitative and Ultra-Sensitive Quantitative Detection.

Aptamer-based probes are pivotal components in various sensing strategies, owing to their exceptional specificity and versatile programmable structure. Nevertheless, numerous aptamer-based probes usually offer only a single function, limiting their capacity to meet the diverse requirements of multi-faceted sensing systems. Here, we introduced supersandwich DNA probes (SSW-DNA), designed and modified on the outer surface of nanochannels with hydrophobic inner walls, enabling dual functionality: qualitative detection for on-site analysis and quantitative detection for precise analysis. The fragmented DNAs resulting from the target recognition, are subsequently identified through lateral flow assays, enabling robust on-site qualitative detection of microcystin-LR with an impressively low limit of detection (LOD) at 0.01 µg/L. Meanwhile, the nanochannels enable highly sensitive quantification of microcystin-LR through the current analysis, achieving an exceptionally low LOD at 2.5×10-7  µg/L, with a broad dynamic range spanning from 1×10-6 to 1×102  µg/L. Furthermore, the process of target recognition introduces just a single potential error propagation, which reduces the overall risk of errors during the entire qualitative and quantitative detection process. This sensing strategy broadens the scope of applications for aptamer-based composite probes, holding promising implications across diverse fields, such as medical diagnosis, food safety, and environmental protection.

A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-flip Pocket for the Treatment of Obesity.

In animals limiting oxygen upregulates hypoxia-inducible factor (HIF) promoting a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs), which like FIH, are 2-oxoglutarate(2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, binding of which promotes a conformational flip of a catalytically important tyrosine, enabling selective inhibition of FIH over other JmjC subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co-culture assays with motor neurons and reprogrammed patient skin-derived astrocytes (iAs) to evaluate the effects of (SP-4-2)-[[2,2'-(1,2-dimethyl-1,2-ethanediylidene)bis[N-methylhydrazinecarbothioamidato-κN2 ,κS]](2-)]-copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co-culture with healthy motor neurons. Using this assay, we identified responding and non-responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM-responders, a metabolic phenotype not observed in non-responders. Pre-treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient-specific cellular and molecular profiles could help improve clinical trial design in the future.

Stochastic Sensing of Dynamic Interactions and Chemical Reactions with Nanopores/Nanochannels.

Nanopore sensing technology is an emerging analysis method with the advantages of simple operation, high sensitivity, fast output and being label free, and it is widely used in protein analysis, gene sequencing, biomarker detection, and other fields. The confined space of the nanopore provides a place for dynamic interactions and chemical reactions between substances. The use of nanopore sensing technology to track these processes in real time is helpful to understand the interaction/reaction mechanism at the single-molecule level. According to nanopore materials, we summarize the development of biological nanopores and solid-state nanopores/nanochannels in the stochastic sensing of dynamic interactions and chemical reactions. The goal of this paper is to stimulate the interest of researchers and promote the development of this field.

Solid-State Nanopore Sensors with Enhanced Sensitivity through Nucleic Acid Amplification.

Solid-state nanopores have wide applications in DNA sequencing, energy conversion and storage, seawater desalination, sensors, and reactors due to their high stability, controllable geometry, and a variety of pore-forming materials. Solid-state nanopore sensors can be used for qualitative and quantitative analyses of ions, small molecules, proteins, and nucleic acids. The combination of nucleic acid amplification and solid-state nanopores to achieve trace detection of analytes is gradually attracting attention. This review outlines nucleic acid amplification strategies for enhancing the sensitivity of solid-state nanopore sensors by summarizing the articles published in the past 10 years. The future development prospects and challenges of nucleic acid amplification in solid-state nanopore sensors are discussed. This review helps readers better understand the field of solid-state nanopore sensors. We believe that solid-state nanopore sensors will break through the bottleneck of traditional detection and become a powerful single-molecule detection platform.

Novel NQO1 substrates bearing two nitrogen redox centers: Design, synthesis, molecular dynamics simulations, and antitumor evaluation.

By analyzing the crystal structure of NQO1, an additional binding region for the ligand was discovered. In this study, a series of derivatives with a novel skeleton bearing two nitrogen redox centers were designed by introducing amines or hydrazines to fit with the novel binding region of NQO1. Compound 24 with a (4-fluorophenyl)hydrazine substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1972 ± 82 µmol NADPH/min/µmol NQO1 and 6.4 ± 0.4 × 106 M-1s-1, respectively. Molecular dynamics (MD) simulation revealed that the distances between the nitrogen atom of the redox centers and the key Tyr128 and Tyr126 residues were 3.5 Å (N1-Tyr128) and 3.4 Å (N2-Tyr126), respectively. Compound 24 (IC50/A549 = 0.69 ± 0.09 µM) showed potent antitumor activity against A549 cells both in vitro and in vivo through ROS generation via NQO1-mediated redox cycling, leading to a promising NQO1-targeting antitumor candidate.

Inhibiting von Hippel‒Lindau protein-mediated Dishevelled ubiquitination protects against experimental parkinsonism.

Dopaminergic neuron degeneration is a hallmark of Parkinson's disease (PD). We previously reported that the inactivation of von Hippel‒Lindau (VHL) alleviated dopaminergic neuron degeneration in a C. elegans model. In this study, we investigated the specific effects of VHL loss and the underlying mechanisms in mammalian PD models. For in vivo genetic inhibition of VHL, AAV-Vhl-shRNA was injected into mouse lateral ventricles. Thirty days later, the mice received MPTP for 5 days to induce PD. Behavioral experiments were conducted on D1, D3, D7, D14 and D21 after the last injection, and the mice were sacrificed on D22. We showed that knockdown of VHL in mice significantly alleviated PD-like syndromes detected in behavioral and biochemical assays. Inhibiting VHL exerted similar protective effects in MPP+-treated differentiated SH-SY5Y cells and the MPP+-induced C. elegans PD model. We further demonstrated that VHL loss-induced protection against experimental parkinsonism was independent of hypoxia-inducible factor and identified the Dishevelled-2 (DVL-2)/ß-catenin axis as the target of VHL, which was evolutionarily conserved in both C. elegans and mammals. Inhibiting the function of VHL promoted the stability of ß-catenin by reducing the ubiquitination and degradation of DVL-2. Thus, in vivo overexpression of DVL-2, mimicking VHL inactivation, protected against PD. We designed a competing peptide, Tat-DDF-2, to inhibit the interaction between VHL and DVL-2, which exhibited pharmacological potential for protection against PD in vitro and in vivo. We propose the therapeutic potential of targeting the interaction between VHL and DVL-2, which may represent a strategy to alleviate neurodegeneration associated with PD.

Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice.

BACKGROUND: Premature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. The aetiology of POI is genetically heterogeneous, with certain double-strand break (DSB) repair genes being implicated in POI. Although non-homologous end joining (NHEJ) is an efficient DSB repair pathway, the functional relationship between this pathway and POI remains unknown. METHODS AND RESULTS: We conducted whole-exome sequencing in a Chinese family and identified a rare heterozygous loss-of-function variant in non-homologous end joining factor 1 (NHEJ1): c.532C>T (p.R178*), which co-segregated with POI and irregular menstruation. The amount of NHEJ1 protein in the proband was half of the normal level, indicating a link between NHEJ1 haploinsufficiency and POI. Furthermore, another rare heterozygous NHEJ1 variant c.500A>G (p.Y167C) was identified in one of 100 sporadic POI cases. Both variants were predicted to be deleterious by multiple in silico tools. In vitro assays showed that knock-down of NHEJ1 in human KGN ovarian cells impaired DNA repair capacity. We also generated a knock-in mouse model with a heterozygous Nhej1 variant equivalent to NHEJ1 p.R178* in familial patients. Compared with wild-type mice, heterozygous Nhej1-mutated female mice required a longer time to first birth, and displayed reduced numbers of primordial and growing follicles. Moreover, these mice exhibited higher sensitivity to DSB-inducing drugs. All these phenotypes are analogous to the progressive loss of ovarian function observed in POI. CONCLUSIONS: Our observations in both humans and mice suggest that NHEJ1 haploinsufficiency is associated with non-syndromic POI, providing novel insights into genetic counselling and clinical prevention of POI.

Association between nineteen dietary fatty acids and hearing thresholds: findings from a nationwide survey.

INTRODUCTION: Hearing loss is a prevalent health concern, and dietary factors, such as fatty acid intake, may play a role in its development. The current study aimed to investigate the association between the intake of dietary fatty acids and hearing thresholds among U.S. adults. METHODS: The researchers examined data from the National Health and Nutrition Examination Survey (NHANES), including 7,623 participants with available dietary fatty acid intake and audiometry data. Dietary fatty acid intake was assessed using dietary recalls, and hearing thresholds were measured using pure-tone audiometry. Multivariate linear regression models and smoothing curve fitting were utilized to explore the associations between dietary fatty acid intake and hearing thresholds, adjusting for relevant covariates. RESULTS: This study reveals a direct association between both low and high frequency pure tone average (PTA) hearing thresholds and the dietary intake of total saturated fatty acids (SFAs) and total polyunsaturated fatty acids (PUFAs). Conversely, the intake of total monounsaturated fatty acids (MUFAs) demonstrates an inverted U-shaped correlation with low-frequency and high-frequency PTA hearing thresholds, having inflection points at 11.91 (energy (%)) and 10.88 (energy (%)), respectively. CONCLUSION: Dietary intake of certain fatty acids may influence hearing thresholds in adults.

A Model of Basement Membrane-Associated Gene Signature Predicts Liver Hepatocellular Carcinoma Response to Immune Checkpoint Inhibitors.

Liver hepatocellular carcinoma (LIHC) is a highly lethal malignant tumor originating from the digestive system, which is a serious threat to human health. In recent years, immunotherapy has shown significant therapeutic effects in the treatment of LIHC, but only for a minority of patients. The basement membrane (BM) plays an important role in the occurrence and development of tumors, including LIHC. Therefore, this study is aimed at establishing a risk score model based on basement membrane-related genes (BMRGs) to predict patient prognosis and response to immunotherapy. First, we defined three patterns of BMRG modification (C1, C2, and C3) by consensus clustering of BMRG sets and LIHC transcriptome data obtained from public databases. Survival analysis showed that patients in the C2 group had a better prognosis, and Gene Set Variation Analysis (GSVA) revealed that the statistically significant pathways were mainly enriched in the C2 group. Moreover, we performed Weighted Correlation Network Analysis (WGCNA) on the above three subgroups and obtained 179 intersecting genes. We further applied function enrichment analyses, and the results demonstrated that they were mainly enriched in metabolism-related pathways. Furthermore, we conducted the LASSO regression analysis and obtained 4 BMRGs (MPV17, GNB1, DHX34, and MAFG) that were significantly related to the prognosis of LIHC patients. We further constructed a prognostic risk score model based on the above genes, which was verified to have good predictive performance for LIHC prognosis. In addition, we analyzed the correlation between the risk score and the tumor immune microenvironment (TIM), and the results showed that the high-risk scoring group tended to be in an immunosuppressed status. Finally, we investigated the relationship between the risk score and LIHC immune function. The results demonstrated that the risk score was closely related to the expression levels of multiple immune checkpoints. Patients in the low-risk group had significantly higher IPS scores, and patients in the high-risk group had lower immune escape and TIDE score. In conclusion, we established a novel risk model based on BMRGs, which may serve as a biomarker for prognosis and immunotherapy in LIHC.

Treatment outcomes of permanent teeth with uncomplicated and complicated crown fractures and factors associated with pulp survival: A retrospective study.

BACKGROUND: Crown fracture is the most common injury in permanent teeth. This study aimed to evaluate the treatment outcomes of permanent teeth with uncomplicated and complicated crown fractures and to investigate potential factors. MATERIALS AND METHODS: This retrospective study included patients who experienced crown fractures in permanent teeth from 2018 to 2021 with at least 12 months of follow-up. All complicated crown fractured teeth were treated with pulpotomy, while for teeth with uncomplicated crown fractures, three treatments (restoration, indirect pulp capping, or pulpotomy) were employed. The chi-square test was used to compare the prognosis of teeth with uncomplicated and complicated crown fractures. Potential factors associated with pulp survival including gender, interval, root development, enamel infraction, mobility, concomitant luxation injury, treatment, and coronal restoration were identified via Cox regression analysis. RESULTS: A total of 307 teeth from 220 children (average age = 9.3 ± 1.4 years; age range, 6-14 years) with a median follow-up of 23 months were included, and 82.1% of all teeth had immature roots. Complicated crown fractured teeth (93.6%, 102/109) had a significantly higher success rate compared with uncomplicated crown fractured teeth (85.4%, 169/198) (p < .05). Pulpotomy (96.9%) had the highest success rate of all treatments for uncomplicated crown fractures, followed by only restoration (85.0%) and indirect pulp capping (76.9%). The success rate of teeth that received pulpotomy was significantly higher than those treated by indirect pulp capping (p < .05). In uncomplicated crown fractures, teeth with Class II mobility were more vulnerable to failure than teeth without abnormal mobility (HR = 34.83; 95% CI, 9.59-126.56; p < .05); teeth that received pulpotomy were less prone to failure than teeth that received indirect pulp capping (HR = 13.53; 95% CI, 1.58-115.72; p < .05). CONCLUSION: Crown fractures treated with conservative pulp treatments had a relatively highly favorable prognosis. The prognosis of uncomplicated crown fractured teeth was impacted by the severity of periodontal injury and treatment strategies. Accurate diagnosis and identification of micro-exposures are important. Dentists should take multiple risk factors into account and select optimal treatment strategies.

Inner Wall and Outer Surface Distinguished Solid-State Nanopores for Sensing.

Solid-state nanopores, inspired by biological nanopores, have the advantages of good mechanical properties, stability, and easy modification. They have attracted wide attention in the fields of sequencing, sensing, molecular sieving, nanofluidic devices, nanoelectrochemistry, and energy conversion. Because of the ion/molecule transport characteristic of the pore, the research on solid-state nanopores mainly focuses on the functional modification of its inner wall. In recent years, the outer surface of nanopores has also attracted the attention of researchers, and the functional elements on the outer surface have the functions of anti-interference and ionic signal enhancement. In this perspective, we review research progress of inner wall and outer surface distinguished solid-state nanopores, highlight their processing and advantages, summarize their functions and applications in sensing, and give insight into further research.

Downregulation of HSPA12A underlies myotoxicity of local anesthetic agent bupivacaine through inhibiting PGC1α-mediated mitochondrial integrity.

Local anesthetics (LAs) are widely used for intraoperative anesthesia and postoperative analgesia. However, LAs (e.g. Bupivacaine) can evoke myotoxicity that closely associated to mitochondrial damage. PGC1a is a mast co-factor for mitochondrial quality control. We have recently demonstrated that PGC1a can be activated by HSPA12A in hepatocytes, suggesting a possibility that HSPA12A protects from LAs myotoxicity through activating PGC1α-mediated mitochondrial integrity. Here, we reported that HSPA12A was downregulated during Bupivacaine-induced myotoxicity in skeletal muscles of mice in vivo and C2c12 myoblast cultures in vitro. Intriguingly, overexpression of HSPA12A attenuated the Bupivacaine-induced C2c12 cell death. We also noticed that the Bupivacaine-induced decrease of glucose consumption and ATP production was improved by HSPA12A overexpression. Moreover, overexpression of HSPA12A in C2c12 cells attenuated the Bupivacaine-induced decrease of mitochondrial contents and increase of mitochondrial fragmentation. The Bupivacaine-induced reduction of PGC1α expression and nuclear localization was markedly attenuated by HSPA12A overexpression. Importantly, pretreatment with a selective PGC1α inhibitor (SR-18292) abolished the protection of HSPA12A from Bupivacaine-induced death and mitochondrial loss in C2c12 cells. Altogether, the findings indicate that downregulation of HSPA12A underlies myotoxicity of Local anesthetic agent Bupivacaine through inhibiting PGC1α-mediated Mitochondrial Integrity. Thus, HSPA12A might represent a viable strategy for preventing myotoxicity of LAs.