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.

A synergistic study of policy and literature on rumor governance.

Rumor governance is an important guarantee for social stability and public safety. Based on the life cycle and crisis cycle model, this paper conducts a synergistic analysis of China's rumor governance policies and regulations and the core scientific research literature on rumor governance in WOS and CNKI. In this paper, we use the TF-IDF algorithm to count the word frequencies of 326 policy and regulation texts, the Jieba-RoBERTa-Kmeans model to cluster high-frequency keywords, and CiteSpace software and the LLR clustering algorithm are utilized to extract and cluster keywords from 391 documents in the WOS database and from 703 documents in the CNKI database. Based on the synergistic analysis of the life cycle model, it is found that the research on policies and regulations precedes the research on literature, and both are in the period of refinement.Based on the synergistic analysis using the co-occurrence comparison of subject terms in the crisis cycle model, it is found that there is a lack of research in the stages of prevention, monitoring, and governance, and this paper proposes the systematic governance mechanism and strategy for crisis resolution that conforms to the trend of life cycle evolution and is synergistic with policy and literature. This study has only selected Chinese policies and regulations, and the proposed governance strategies have not yet been verified in practice; future research can expand the scope and depth of the study and conduct empirical research and pilot projects.

Commercial Nafion Membranes for Harvesting Osmotic Energy from Proton Gradients that Exceed the Commercial Goal of 5.0 W/m2.

Osmotic energy from proton gradients in industrial acidic wastewater can be harvested and converted to electricity through membranes, making it a renewable and sustainable power source. However, the currently designed membranes for harvesting proton gradient energy in acidic wastewater cannot simultaneously achieve excellent chemical/mechanical stability and high power density under a large-scale area and require high cost and complex operations. Here, we demonstrate that commercial Nafion membranes with high chemical/mechanical stability and proton transport selectivity can generate a power density of 5.1 W/m2 for harvesting osmotic energy from proton gradients under a test area of 0.2 mm2, which exceeds the commercial goal of 5.0 W/m2. Even under a test area of 12.5 mm2, a power density of 2.1 W/m2 can be achieved under a strong acid condition. In addition, the heat can greatly promote proton transport, and the power density is increased, i.e., 8.1 W/m2 at 333 K (5.1 W/m2 at 293 K) under a test area of 0.2 mm2. By matching membranes with ion selectivity, our work demonstrates the potential of Nafion membranes for harvesting proton gradient energy in acidic wastewater and provides an approach for large-scale conversion of osmotic energy.

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.

Sentiment analysis of video danmakus based on MIBE-RoBERTa-FF-BiLSTM.

Danmakus are user-generated comments that overlay on videos, enabling real-time interactions between viewers and video content. The emotional orientation of danmakus can reflect the attitudes and opinions of viewers on video segments, which can help video platforms optimize video content recommendation and evaluate users' abnormal emotion levels. Aiming at the problems of low transferability of traditional sentiment analysis methods in the danmaku domain, low accuracy of danmaku text segmentation, poor consistency of sentiment annotation, and insufficient semantic feature extraction, this paper proposes a video danmaku sentiment analysis method based on MIBE-RoBERTa-FF-BiLSTM. This paper constructs a "Bilibili Must-Watch List and Top Video Danmaku Sentiment Dataset" by ourselves, covering 10,000 positive and negative sentiment danmaku texts of 18 themes. A new word recognition algorithm based on mutual information (MI) and branch entropy (BE) is used to discover 2610 irregular network popular new words from trigrams to heptagrams in the dataset, forming a domain lexicon. The Maslow's hierarchy of needs theory is applied to guide the consistent sentiment annotation. The domain lexicon is integrated into the feature fusion layer of the RoBERTa-FF-BiLSTM model to fully learn the semantic features of word information, character information, and context information of danmaku texts and perform sentiment classification. Comparative experiments on the dataset show that the model proposed in this paper has the best comprehensive performance among the mainstream models for video danmaku text sentiment classification, with an F1 value of 94.06%, and its accuracy and robustness are also better than other models. The limitations of this paper are that the construction of the domain lexicon still requires manual participation and review, the semantic information of danmaku video content and the positive case preference are ignored.

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.

Magneto-Induced Janus Adhesive-Tough Hydrogels for Wearable Human Motion Sensing and Enhanced Low-Grade Heat Harvesting.

Janus hydrogels with different properties on the two surfaces have considerable potential in the field of material engineering applications. Various Janus hydrogels have been developed, but there are still some problems, such as stress mismatch caused by the double-layer structure and Janus failure caused by material diffusion in the gradient structure. Here, we report a Janus adhesive-tough hydrogel with polydopamine-decorated Fe3O4 nanoparticles (Fe3O4@PDA) at one side induced by magnetic field to avoid uncontrollable material diffusion in the cross-linking polymerization of acrylamide with alginate-calcium. The magneto-induced Janus (MIJ) hydrogel has an adhesive surface and a tough bulk without an obvious interface to avoid stress mismatch. Due to the intrinsic dissipative matrix and the abundant catechol groups on the adhesive surface, it shows strong adhesion onto various substrates. The MIJ hydrogel has high sensitivity (GF = 0.842) in detecting tiny human motion. Owing to the synergy of Fe3O4@PDA-enhanced interfacial adhesion and heat transfer, it is possible to quickly generate effective temperature differences when adhering to human skin. The MIJ hydrogel achieves a Seebeck coefficient of 13.01 mV·K-1 and an output power of 462.02 mW·m-2 at a 20 K temperature difference. This work proposes a novel strategy to construct Janus hydrogels for flexible wearable devices in human motion sensing and low-grade heat harvesting.

HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that, during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A KO in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion and, ultimately, improving cardiomyocyte survival to attenuate MI/R injury.

Trends and driving forces of agricultural carbon emissions: A case study of Anhui, China.

To facilitate accurate prediction and empirical research on regional agricultural carbon emissions, this paper uses the LLE-PSO-XGBoost carbon emission model, which combines the Local Linear Embedding (LLE), Particle Swarm Algorithm (PSO) and Extreme Gradient Boosting Algorithm (XGBoost), to forecast regional agricultural carbon emissions in Anhui Province under different scenarios. The results show that the regional agricultural carbon emissions in Anhui Province generally show an upward and then downward trend during 2000-2021, and the regional agricultural carbon emissions in Anhui Province in 2030 are expected to fluctuate between 11,342,100 tones and 14,445,700 tones under five different set scenarios. The projections of regional agricultural carbon emissions can play an important role in supporting the development of local regional agriculture, helping to guide the input and policy guidance of local rural low-carbon agriculture and promoting the development of rural areas towards a resource-saving and environment-friendly society.

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.

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.

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.

HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis.

INTRODUCTION: Cardiac fibrosis is the main driver for adverse remodeling and progressive functional decline in nearly all types of heart disease including myocardial infarction (MI). The activation of cardiac fibroblasts (CF) into myofibroblasts is responsible for cardiac fibrosis. Unfortunately, no ideal approach for controlling CF activation currently exists. OBJECTIVES: This study investigated the role of Heat shock protein A12A (HSPA12A), an atypical member of the HSP70 family, in CF activation and MI-induced cardiac fibrosis. METHODS: Primary CF and Hspa12a knockout mice were used in the experiments. CF activation was indicated by the upregulation of myofibroblast characters including alpha-Smooth muscle actin (αSMA), Collagen, and Fibronectin. Cardiac fibrosis was illustrated by Masson's trichrome and picrosirius staining. Cardiac function was examined using echocardiography. Glycolytic activity was indicated by levels of extracellular lactate and the related protein expression. Protein stability was examined following cycloheximide and MG132 treatment. Protein-protein interaction was examined by immunoprecipitation-immunoblotting analysis. RESULTS: HSPA12A displayed a high expression level in quiescent CF but showed a decreased expression in activated CF, while ablation of HSPA12A in mice promoted CF activation and cardiac fibrosis following MI. HSPA12A overexpression inhibited the activation of primary CF through inhibiting glycolysis, while HSPA12A knockdown showed the opposite effects. Moreover, HSPA12A upregulated the protein expression of transcription factor p53, by which mediated the HSPA12A-induced inhibition of glycolysis and CF activation. Mechanistically, this action of HSPA12A was achieved by acting as a scaffolding protein to bind p53 and ubiquitin specific protease 10 (USP10), thereby promoting the USP10-mediated p53 protein stability and the p53-medicated glycolysis inhibition. CONCLUSION: The present study provided clear evidence that HSPA12A is a novel endogenous inhibitor of CF activation and cardiac fibrosis. Targeting HSPA12A in CF could represent a promising strategy for the management of cardiac fibrosis in patients.

Risk Prediction of Diabetic Foot Amputation Using Machine Learning and Explainable Artificial Intelligence.

BACKGROUND: Diabetic foot ulcers (DFUs) are serious complications of diabetes which can lead to lower extremity amputations (LEAs). Risk prediction models can identify high-risk patients who can benefit from early intervention. Machine learning (ML) methods have shown promising utility in medical applications. Explainable modeling can help its integration and acceptance. This study aims to develop a risk prediction model using ML algorithms with explainability for LEA in DFU patients. METHODS: This study is a retrospective review of 2559 inpatient DFU episodes in a tertiary institution from 2012 to 2017. Fifty-one features including patient demographics, comorbidities, medication, wound characteristics, and laboratory results were reviewed. Outcome measures were the risk of major LEA, minor LEA and any LEA. Machine learning models were developed for each outcome, with model performance evaluated using receiver operating characteristic (ROC) curves, balanced-accuracy and F1-score. SHapley Additive exPlanations (SHAP) was applied to interpret the model for explainability. RESULTS: Model performance for prediction of major, minor, and any LEA event achieved ROC of 0.820, 0.637, and 0.756, respectively, with XGBoost, XGBoost, and Gradient Boosted Trees algorithms demonstrating best results for each model, respectively. Using SHAP, key features that contributed to the predictions were identified for explainability. Total white cell (TWC) count, comorbidity score and red blood cell count contributed highest weightage to major LEA event. Total white cell, eosinophils, and necrotic eschar in the wound contributed most to any LEA event. CONCLUSIONS: Machine learning algorithms performed well in predicting the risk of LEA in a patient with DFU. Explainability can help provide clinical insights and identify at-risk patients for early intervention.

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 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.

Rare variants in GPR3 in POI patients: a case series with review of literature.

BACKGROUND: Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of the cases can be explained by genetic causes. G protein-coupled receptor 3 (GPR3) plays an important role in oocyte arrest, and Gpr3-deficient mice exhibited POI-like phenotypes. CASE PRESENTATION: We identified two heterozygous missense variants of GPR3: NM_005281: c.C973T (p.R325C) and c.G772A (p.A258T) in two sporadic Han Chinese POI cases through whole exome sequencing and genetic analysis. The two patients were diagnosed as POI in their late 20s, presenting elevated serum levels of follicle stimulating hormone and secondary amenorrhea. Both variants are very rare in the population databases of ExAC, gnomAD and PGG.Han. The affected amino acids are conserved across species and the mutated amino acids are predicted deleterious with bioinformatics prediction tools and the protein three-dimensional structure analysis. CONCLUSIONS: It is the first report of rare GPR3 variants associated with POI women, providing an important piece of evidence for GPR3 as a candidate gene which should be screened in POI. This finding suggested the necessity of including GPR3 in etiology study and genetic counseling of POI patients.

Structure-guided optimisation of N-hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-α.

The human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) and HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans via catalysing hydroxylation of the α-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the N-hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition. Structure-guided optimisation resulted in the discovery of N-hydroxythiazole derivatives that manifest substantially improved selectivity for FIH inhibition over PHD2 and other 2OG oxygenases, including Jumonji-C domain-containing protein 5 (∼25-fold), aspartate/asparagine-ß-hydroxylase (>100-fold) and histone Nε-lysine demethylase 4A (>300-fold). The optimised N-hydroxythiazole-based FIH inhibitors modulate the expression of FIH-dependent HIF target genes and, consistent with reports that FIH regulates cellular metabolism, suppressed lipid accumulation in adipocytes. Crystallographic studies reveal that the N-hydroxythiazole derivatives compete with both 2OG and the substrate for binding to the FIH active site. Derivatisation of the N-hydroxythiazole scaffold has the potential to afford selective inhibitors for 2OG oxygenases other than FIH.

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.