Outcomes Following Different Management of Mycotic Infrarenal Abdominal Aortic Aneurysms.

OBJECTIVE: The objective was to present our experience on managing mycotic infrarenal abdominal aortic aneurysm (MIAAA) through a retrospective cohort study. METHODS: Data of patients with MIAAA managed in our center from July 2016 to October 2022 were retrospectively analyzed. The diagnosis of MIAAA was made based on: (1) preoperative clinical signs of infection; (2) elevated serologic infection parameters; (3) para-aneurysmal infection features on enhanced computed tomography; and (4) positive blood or tissue cultures. All the patients received standard antibiotic therapy. Surgical management including endovascular aneurysm repair (EVAR), initial EVAR followed by open re-operation, and initial open surgical repair (OSR) were conducted according to disease seriosity, physical condition, and patient's will. Infection index and clinical outcome were evaluated during the follow-up time. RESULTS: A total of 23 patients (21 men; averaged=66.3 years, range=49-79 years) were included, with a mean follow-up time of 19.9 months (range=1-75 months). Bacteria culture from blood or tissue specimen was positive in 15 patients (Salmonella, n=8; Escherichia coli, n=3; methicillin-sensitive Staphylococcus aureus [MSSA], n=1; Klebsiella pneumoniae, n=1; Staphylococcus epidermidis, n=1; Mycobacterium tuberculosis, n=1). Seven patients received OSR as the initial surgical intervention, whereas 14 patients chose EVAR instead. The 2 conservatively managed patients (refused surgery) died within 30 days. The 7 patients who received initial OSR survived till now. Among the 14 patients who underwent initial EVAR, infection deteriorated without exception (14/14, 100%). Three of these patients refused re-operation and died within 6 months. Eleven patients received secondary surgical intervention (10 cases of aneurysm and endograft resection, thorough debridement, subclavian to bi-femoral artery bypass, or in situ aorta reconstruction; 1 case of laparoscopic debridement) and 7 survived the follow-up time. The overall mortality rate was 39.1% (9/23). The mortality rates differed greatly following different intervention methods (merely antibiotic management, 100%; initial open operation, 0%; initial EVAR without secondary operation, 100%; initial EVAR plus secondary operation, 36.4%). CONCLUSIONS: Open surgical repair is still the first choice for hemodynamically stable and low-risk patients. Merely EVAR is related with disastrous results, which should be reserved as a temporary alternative for patients with ruptured aneurysms, hemodynamic instability or high surgical risk, and followed by timely secondary OSR. CLINICAL IMPACT: The management of mycotic or primary-infected aortic aneurysm is challenging; treatment remains controversial. Our center has reviewed our experience over the past 6 years and found that open surgical repair is still the first choice for hemodynamically stable and low-risk patients. Merely endovascular aneurysm repair (EVAR) is related with disastrous results, which should be reserved as a temporary alternative for patients with ruptured aneurysms, hemodynamic instability or high surgical risk, and followed by timely secondary open surgical repair.

Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.

Nickel (Ni) and its compounds are common, widely distributed components of hazardous waste in the chemical industry. Excessive exposure to Ni can cause kidney damage in humans and animals. We investigated the impact of Ni on renal mitochondria using in vivo and in vitro models of Ni nephrotoxicity, and explored the Ni nephrotoxic mechanism. We showed that nickel chloride (NiCl2) damaged the renal mitochondria, causing mitochondrial swelling, breakage of the mitochondrial cristae, increased levels of mitochondrial reactive oxygen species (mt-ROS), and depolarization of the mitochondrial membrane potential (MMP). The levels of the mitochondrial respiratory chain complexes I-IV were reduced in the kidneys of mice treated with NiCl2. In addition, NiCl2 treatment inhibited mitochondrial biogenesis in renal cells by down-regulating mRNA and the protein expression of TFAM, PGC-1α, and NRF1. Moreover, NiCl2 reduced the levels of the proteins involved in mitochondrial fusion, including Mfn1 and Mfn2, while significantly augmenting the levels of the proteins Fis1 and Drip1 involved in mitochondrial fission in renal cells. Taken together, these results suggested that NiCl2 inhibited mitochondrial biogenesis, suppressed mitochondrial fusion, and promoted mitochondrial fission, resulting in mitochondrial dysfunction in renal cells, ultimately causing renal injury. This study provided novel insights into the mechanisms of nephrotoxicity of Ni and new ideas for the development of targeted treatments for Ni-induced kidney injury.

Nickel induces epithelial-mesenchymal transition in pulmonary fibrosis in mice via activation of the oxidative stress-mediated TGF-ß1/Smad signaling pathway.

Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni-induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real-time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up-regulation of α-smooth muscle actin (α-SMA), and collagen-1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial-mesenchymal transition (EMT) and the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway; up-regulation of protein and mRNA expression of TGF-ß1, p-Smad2, p-Smad3, vimentin, and N-cadherin; and down-regulation of protein and mRNA expression of E-cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co-treatment with the effective antioxidant and free radical scavenger N-acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2-induced PF. The addition of NAC significantly mitigated NiCl2-induced PF, and reversed activation of the TGF-ß1/Smad signaling pathway and EMT. NiCl2-induced PF was therefore shown to be due to EMT activation via the TGF-ß1/Smad signaling pathway, mediated by oxidative stress.

Icariin ameliorates osteoporosis in ovariectomized rats by targeting Cullin 3/Nrf2/OH pathway for osteoclast inhibition.

Osteoporosis, characterized by low bone mass and bone microarchitecture breakdown, has become a growing public health problem. The increase in oxidative stress could lead to an imbalance between osteoblasts-mediated osteogenesis and osteoclast-mediated bone resorption, which gives rise to osteoporosis. Nrf2 is a master transcription factor that regulates oxidative stress and has recently been reported to take part in the development of osteoporosis. Icariin, a leading active flavonoid in herbal Epimedium pubescens, has significant antioxidant activity in and is widely applied for treating bone diseases. In this study, we aimed to explore the effect of icariin on osteoclastogenesis and its potential mechanism from the perspective of oxidative stress inhibition, using ovariectomized (OVX) rats and RANKL-induced RAW264.7 cells. Our results demonstrated that icariin-treated OVX rats exhibited higher bone density, fewer tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and lower ROS levels in bone tissues than vehicle-treated OVX rats. Also, icariin suppressed osteoclast differentiation and inhibited the expression of osteoclastogenesis-related genes, such as NFATc1, Ctsk, Trap, and c-Fos, in RANKL-induced RAW264.7 cells. Icariin also reduced intracellular ROS levels by increasing the expression of nuclear Nrf2 and HO-1. Further mechanistic studies showed icariin inhibited Cullin 3 expression and could delay Nrf2 degradation by reducing the ubiquitination of endogenous Nrf2 in RANKL-stimulated RAW264.7 cells, and these effects were markedly reversed by cullin three overexpression. These findings suggest icariin alleviated osteoporosis by suppressing osteoclastogenesis via targeting the Cullin 3/Nrf2/OH signaling pathway. Our study implied that icariin may be a potential candidate to treat osteoporosis.

The mechanism of nickel-induced autophagy and its role in nephrotoxicity.

Nickel (Ni), an environmental health hazard, is nephrotoxic to humans, but the exact mechanism is unknown. This study aims to identify whether nephrotoxicity is associated with autophagy. Here, nickel chloride (NiCl2) increased autophagy in TCMK-1 cells. NiCl2 induces autophagy through Akt and AMPK/mTOR pathways. Next, oxidative stress was investigated in NiCl2-induced autophagy. The findings demonstrated that the antioxidant (NAC) or mitochondrial targeted antioxidant (Mito-TEMPO) attenuated NiCl2-induced autophagy, reversed the influence on AMPK-mTOR and Akt pathways. Additionally, our study examined the role of autophagy in NiCl2-induced nephrotoxicity. Autophagy inhibition with 3-MA could inhibit cell viability and increase apoptosis in the TCMK-1 cells, however, autophagy promotion with rapamycin relieved cytotoxicity and decreased apoptosis. Additionally, co-treatment with Z-VAD-FMK reduced cytotoxicity, but did not affect autophagy. Besides, NiCl2 can increase the level of mitophagy in vivo and vitro. Mitophagy inhibition could inhibit cell viability and increase apoptosis in the TCMK-1 cells, whereas, promotion of mitophagy could increase cell viability and decrease apoptosis. In summary, above-mentioned results showed that NiCl2 induces autophagy in TCMK-1 cells through oxidative stress-dependent AMPK/AKT-mTOR pathway, autophagy plays a role in reducing NiCl2-induced renal toxicity, and a major mechanism in autophagy's inhibitory effect on NiCl2-induced apoptosis may be mitophagy.

A neural network with a human learning paradigm for breast fibroadenoma segmentation in sonography.

BACKGROUND: Breast fibroadenoma poses a significant health concern, particularly for young women. Computer-aided diagnosis has emerged as an effective and efficient method for the early and accurate detection of various solid tumors. Automatic segmentation of the breast fibroadenoma is important and potentially reduces unnecessary biopsies, but challenging due to the low image quality and presence of various artifacts in sonography. METHODS: Human learning involves modularizing complete information and then integrating it through dense contextual connections in an intuitive and efficient way. Here, a human learning paradigm was introduced to guide the neural network by using two consecutive phases: the feature fragmentation stage and the information aggregation stage. To optimize this paradigm, three fragmentation attention mechanisms and information aggregation mechanisms were adapted according to the characteristics of sonography. The evaluation was conducted using a local dataset comprising 600 breast ultrasound images from 30 patients at Suining Central Hospital in China. Additionally, a public dataset consisting of 246 breast ultrasound images from Dataset_BUSI and DatasetB was used to further validate the robustness of the proposed network. Segmentation performance and inference speed were assessed by Dice similarity coefficient (DSC), Hausdorff distance (HD), and training time and then compared with those of the baseline model (TransUNet) and other state-of-the-art methods. RESULTS: Most models guided by the human learning paradigm demonstrated improved segmentation on the local dataset with the best one (incorporating C3ECA and LogSparse Attention modules) outperforming the baseline model by 0.76% in DSC and 3.14 mm in HD and reducing the training time by 31.25%. Its robustness and efficiency on the public dataset are also confirmed, surpassing TransUNet by 0.42% in DSC and 5.13 mm in HD. CONCLUSIONS: Our proposed human learning paradigm has demonstrated the superiority and efficiency of ultrasound breast fibroadenoma segmentation across both public and local datasets. This intuitive and efficient learning paradigm as the core of neural networks holds immense potential in medical image processing.

Koumine inhibits RANKL-induced ubiquitination and NF-κB activation to prevent ovariectomy and aging-induced bone loss.

Osteoporosis (OP) is a bone remodeling disease characterized by an imbalance between bone resorption and formation. Osteoclasts are the primary therapeutic targets for treating bone destruction. Koumine (KM), the most bioactive component in Gelsemium alkaloids, exhibits antitumor, immunosuppressive, anti-inflammatory, and analgesic properties. However, the effects of bone loss have not been well studied. This study conducted in vitro and in vivo verification experiments on KM. The results showed that KM inhibited bone resorption and tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts development by mature osteoclasts in a dose-dependent manner. Moreover, KM prevented OVX-induced OP in vivo and potentially inhibited ubiquitination, a process closely related to various biological activities, including protein interaction, transcription, and transmembrane signal transduction regulation, especially within the nuclear factor-κB (NF-κB) pathway. Previous studies have demonstrated that several proteins ubiquitination promotes osteoclastogenesis, our study indicated that KM inhibits early NF-κB activation and receptor activator of NF-κB ligand induced ubiquitination, a critical factor in osteoclast differentiation. In conclusion, our research suggests that KM holds potential as an effective therapeutic agent for OP.

Sommerlad-Furlow modified palatoplasty: A retrospective study.

The purpose of this study was to introduce the surgical process of Sommerlad-Furlow modified (S-F) palatoplasty and compare its surgical and functional outcomes with conventional Sommerlad (S) palatoplasty. Patients with non-syndromic cleft palate who had undergone either S-F palatoplasty or S palatoplasty were retrospectively reviewed. Data on the outcomes of velopharyngeal function and postsurgical palatal fistula incidence were collected for all patients. Data for preselected factors, including gender, age at palatoplasty, and cleft type, were also collected. Chi-square tests were conducted. 1254 patients were included. The postsurgical velopharyngeal competence (VPC) rate after S-F palatoplasty was significantly higher than after S palatoplasty (total, 70.5% vs 57.9%, p < 0.0001; age ≤ 1, 87.0% vs 69.2%, p < 0.0001; 1 < age ≤ 2, 78.3% vs 69.3%, p = 0.0479). With regard to different types of cleft palate, the postsurgical VPC rates after S-F palatoplasty were all significantly higher than for S palatoplasty in all patients younger than 2 years of age (complete cleft palate, 78.7% vs 62.4%, p = 0.0016; hard and soft palate cleft, 84.4% vs 74.8%, p = 0.0172; submucosal cleft and soft palate cleft, 96.6% vs 68.4%, p = 0.0114). The postoperative fistula rate after S-F palatoplasty was 4.3%. This modified palatoplasty technique provided adequate cleft palate closure, with satisfactory speech outcomes and low fistula rates, while older age at palatoplasty may affect the postsurgical outcomes. Within the limitations of the study it seems that the Sommerlad-Furlow modified technique is an option for cleft palate repair.

Autophagy-mediated ferroptosis involved in nickel-induced nephrotoxicity in the mice.

Nickel, as a widely polluted metal, has been shown nephrotoxicity. Ferroptosis is a new type of cell death driven by iron-dependent lipid peroxidation. Our study found that nickel chloride (NiCl2) induced ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl2 treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl2. Moreover, NiCl2 increased COX-2 protein levels, decreased SLC7A11 and GPX4 protein levels, and elevated Ptgs2 mRNA levels. Next, the mechanism of Ni-induced ferroptosis was investigated. The results showed that NiCl2 induced autophagy in TCMK-1 cells, which promoted ferroptosis induced by NiCl2. Furthermore, the data of autophagy activation or inhibition experiment showed that autophagy facilitated ferroptosis through the degradation of the iron regulation protein NCOA4 and FTH1. Otherwise, iron chelator DFOM treatment inhibited ferroptosis induced by NiCl2. Finally, ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl2. To sum up, our above results showed that ferroptosis is involved in NiCl2-induced nephrotoxicity, and NiCl2 induces autophagy-dependent ferritin degradation, releases iron ions, leads to iron overload, and induces ferroptosis. This study supplies a new theoretical foundation for the study of nickel and renal toxicity.

Exploring the shared gene signatures of smoking-related osteoporosis and chronic obstructive pulmonary disease using machine learning algorithms.

Objectives: Cigarette smoking has been recognized as a predisposing factor for both osteoporosis (OP) and chronic obstructive pulmonary disease (COPD). This study aimed to investigate the shared gene signatures affected by cigarette smoking in OP and COPD through gene expression profiling. Materials and methods: Microarray datasets (GSE11784, GSE13850, GSE10006, and GSE103174) were obtained from Gene Expression Omnibus (GEO) and analyzed for differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) regression method and a random forest (RF) machine learning algorithm were used to identify candidate biomarkers. The diagnostic value of the method was assessed using logistic regression and receiver operating characteristic (ROC) curve analysis. Finally, immune cell infiltration was analyzed to identify dysregulated immune cells in cigarette smoking-induced COPD. Results: In the smoking-related OP and COPD datasets, 2858 and 280 DEGs were identified, respectively. WGCNA revealed 982 genes strongly correlated with smoking-related OP, of which 32 overlapped with the hub genes of COPD. Gene Ontology (GO) enrichment analysis showed that the overlapping genes were enriched in the immune system category. Using LASSO regression and RF machine learning, six candidate genes were identified, and a logistic regression model was constructed, which had high diagnostic values for both the training set and external validation datasets. The area under the curves (AUCs) were 0.83 and 0.99, respectively. Immune cell infiltration analysis revealed dysregulation in several immune cells, and six immune-associated genes were identified for smoking-related OP and COPD, namely, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), tissue-type plasminogen activator (PLAT), sodium channel 1 subunit alpha (SCNN1A), sine oculis homeobox 3 (SIX3), sperm-associated antigen 9 (SPAG9), and vacuolar protein sorting 35 (VPS35). Conclusion: The findings suggest that immune cell infiltration profiles play a significant role in the shared pathogenesis of smoking-related OP and COPD. The results could provide valuable insights for developing novel therapeutic strategies for managing these disorders, as well as shedding light on their pathogenesis.

Focused ultrasound ablation surgery for multiple breast fibroadenomas: pathological and follow-up results.

OBJECTIVE: To investigate the histopathological findings and follow-up outcome of focused ultrasound ablation surgery (FUAS) treatment of multiple fibroadenomas (FA). METHODS: A total of 20 patients with 101 multiple FAs were enrolled. After one session FUAS ablation, 21 lesions (≥15.0 mm) were surgically removed within one week for histopathological analysis, including 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, H&E staining, nicotinamide adenine dinucleotide (NADH) -flavretin enzyme staining, Transmission electron microscope (TEM) and scanning electron microscope (SEM). The remaining 80 lesions were followed up at 3, 6 and 12 months after treatment. RESULTS: All ablation procedures were performed successfully. Pathologic findings showed that irreversible damage of FA was confirmed. TTC, H&E and NADH staining and TEM/SEM demonstrated tumor cell death and tumor structural destruction at the gross, cellular, and subcellular levels, respectively. The median shrinkage rate at 12 months post-FUAS was 66.4 (43.6, 89.5) %. CONCLUSION: Histopathological analysis for FAs after FUAS treatment proved that FUAS could effectively induce irreversible coagulative necrosis of FA, and the tumor volume would gradually shrink in follow-up. FUAS was safe and effective to treat multiple FAs with good cosmesis.Key pointsThis study was the first study of detailed histopathological analysis for FAs after FUAS treatment.FUAS can effectively induce irreversible coagulative necrosis of fibroadenoma cells.FUAS ablation of multiple fibroadenomas is safe and effective.

Rational Construction of a Novel Bioluminescent Substrate for Sensing the Tumor-Associated Hydrolase Notum.

Notum, one of the key serine hydrolases in mammals, hydrolyzes the palmitoleoyl moieties of many important proteins and modulates multiple signaling pathways including Wnt/ß-catenin signaling. Notum is tightly associated with multiple human diseases, but the reliable and practical tools for sensing Notum activities in complex biological systems are rarely reported. Herein, an efficient strategy was used to rationally construct a specific bioluminescent substrate for Notum. Following computer-aided molecular design and experimental verification, octanoyl luciferin (OL) was selected as the optimum substrate for human Notum, with excellent specificity, high detection sensitivity and high signal-to-noise ratio. Under physiological conditions, OL was readily hydrolyzed by Notum or Notum-containing biological specimens to release d-luciferin that could be easily detected by various fluorescence devices in the presence of luciferase. The applicability of OL for real-time sensing native Notum was examined in living cells, extracellular matrix, and tissue preparations. OL was also used for constructing a high-throughput assay for screening of Notum inhibitors, while a natural compound (bergapten) was newly identified as a potent Notum inhibitor. Collectively, this study devises a reliable and easy-to-use tool for sensing Notum activities in biological systems, which will strongly facilitate hNotum-associated fundamental studies, disease diagnosis, and drug discovery.

Evaluation of Postoperative Outcomes in Two Cleft Palate Repair Techniques without Relaxing Incisions.

BACKGROUND: A modified palatoplasty was established by incorporating the designs of both Sommerlad and Furlow techniques in addition to a novel incision on the medial pterygoid plate's surface, named the Sommerlad-Furlow modified technique. Thus, this study aimed to evaluate the clinical and functional outcomes of the Sommerlad-Furlow modified technique against an accepted standard, the Furlow technique. METHODS: A retrospective review was conducted for 212 consecutive nonsyndromic cleft palate patients who underwent Sommerlad-Furlow ( n = 106) and Furlow ( n = 106) repairs without relaxing incision on the hard palate between 2011 and 2016. The success of surgical procedures was estimated by the rate of postoperative fistula, speech outcomes, and velopharyngeal insufficiency (VPI)-related quality of life. The demographic and surgical data, including sex, age, cleft type, cleft width, and follow-up period were recorded. RESULTS: There was no statistically significant difference between the two treatment groups regarding demographic and surgical data, except the cleft width ( P < 0.001). The incidence of the fistula was 7.5% and 6.6% after the Sommerlad-Furlow and Furlow procedures, respectively. The two groups showed no significant differences in speech outcomes, and adequate velopharyngeal function was found in 84% and 82.1% in Sommerlad-Furlow and Furlow procedures, respectively. Besides, the rate of severe VPI was slightly lower in Sommerlad-Furlow (0.9%) than in Furlow (2.8%) procedures. Moreover, an adequate VPI-related quality of life was found in 80.4% of the Sommerlad-Furlow group and 78.6% of the Furlow group. CONCLUSION: The Sommerlad-Furlow technique has obtained acceptable postoperative outcomes and could be a choice for cleft palate repair, especially in wider clefts. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Nickel induces hepatotoxicity by mitochondrial biogenesis, mitochondrial dynamics, and mitophagy dysfunction.

Nickel (Ni) is an important and widely hazardous chemical industrial waste. Excessive Ni exposure could cause multi-organs toxicity in human and animals. Liver is the major target organ of Ni accumulation and toxicity, however, the precise mechanism is still unclear. In this study, nickel chloride (NiCl2 )-treatment induced hepatic histopathological changes in the mice, and, transmission electron microscopy results showed mitochondrial swollen and deformed of hepatocyte. Next, the mitochondrial damages including mitochondrial biogenesis, mitochondrial dynamics, and mitophagy were measured after NiCl2 administration. The results showed that NiCl2 suppressed mitochondrial biogenesis by decreasing PGC-1α, TFAM, and NRF1 protein and mRNA expression levels. Meanwhile, the proteins involved in mitochondrial fusion were reduced by NiCl2 , such as Mfn1 and Mfn2, however, mitochondrial fission proteins Drip1 and Fis1 were significantly increased. The up-regulation of mitochondrial p62 and LC3II expression indicated that NiCl2 increased mitophagy in the liver. Moreover, the receptor-mediated mitophagy and ubiquitin (Ub)-dependent mitophagy were detected. NiCl2 promoted PINK1 accumulation and Parkin recruitment on mitochondria. And, the receptor proteins of mitophagy Bnip3 and FUNDC1 were increased in the NiCl2 -treated mice liver. Overall, these results show that NiCl2 could induce mitochondria damage in the liver of mice, and, dysfunction of mitochondrial biogenesis, mitochondrial dynamics and mitophagy involved in the molecular mechanism of NiCl2 -induced hepatotoxicity.

New insights into the substrate inhibition of human 17ß-hydroxysteroid dehydrogenase type 1.

Human type 1 17ß-hydroxysteroid dehydrogenase (17ß-HSD1),a member of the short-chain dehydrogenase/reductase family, catalyzes the last step in the bioactivation of the most potent estrogen estradiol with high specificity and is thus involved in estrogen-dependent diseases. As an oxidoreductase, 17ß-HSD1 can utilize both triphosphate and diphosphate cofactors in reaction at the molecular level, but more specific with triphosphate cofactor. The NADPH is much higher than NADP+ in living cells leading to preliminary reduction action. The enzyme also showed substrate-induced inhibition unprecedented in other members of 17ß-HSDs. Our previous study elucidated the structural mechanism of substrate inhibition is due to the reversely bound estrone (E1) in the substrate-binding pocket of the enzyme resulting in a dead-end complex. However, the effect of the cofactor preference on the substrate inhibition of the enzyme is not yet clear. In the present study, we solved the ternary crystal structures of 17ß-HSD1 in complex with E1 and cofactor analog NAD+ . Combined with molecular dynamics simulation using the enzyme with NADH/NADPH and different oriented E1 (normally oriented, E1N; reversely oriented, E1R), such ternary structure provides a complete picture of enzyme-substrate-cofactor interactions. The results reveal that different cofactors and substrate binding mode affect the allosteric effect between the two subunits of the enzyme. And the results from MD simulations confirmed that His221 plays a key role in the formation of dead-end complex in NADPH complex, and the absence of stable interaction between His221 and E1R in the NADH complex should be the main reason for its lack of substrate inhibition.

Screening of key biomarkers in osteoporosis: Evidence from bioinformatic analysis.

OBJECTIVE: To analyze the expression characteristics of osteoporosis-related genes by bioinformatics and elucidate the pathogenesis of osteoporosis. METHODS: The differentially expressed genes (DEGs), microRNA (miRNA), and genes with differentially methylated regions (DMRS) in promoters were identified. The protein-protein interaction (PPI) network was constructed and performed. The Clue Gene Ontology analysis and miRNA-mRNA (messenger RNA) regulatory network were constructed using Cytoscape. RESULTS: Fifty-nine DEGs, 10 differential miRNAs, and 2083 genes with DMRs were screened out. The Proteasome-Modulator (PSMD) family proteins and estrogen receptor 1 (ESR1) are vital for the PPI analysis of DEGs. The interaction network of the Smad3 protein showed that the degree of connection to ESR1, PSMD11, and transcription factor 4 (TCF4) is very high. Homo sapiens (hsa)-miR-106b-5p was differential and regulated TCF4 through building the miRNA-mRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of DEGs focused on vascular smooth muscle contraction, thyroid hormone signaling pathway, and estrogen signaling pathway. The Gene Ontology (GO) function analysis of genes with DMRs in promoters was primarily concentrated in the cell differentiation, positive regulation of CDP-diacylglycerol-serine O-phosphatidyltransferase activity, and positive regulation of C-palmitoyltransferase activity. The KEGG enrichment of genes with DMRs in promoters largely focused on glycerol phospholipid metabolism, histidine metabolism, Adenosine 5'-monophosphate-activated protein kinase signaling pathway, Hedgehog signaling pathway, and mRNA surveillance pathway. CONCLUSION: Hsa-miRNA-106b-5p regulates bone formation and the pathogenesis of osteoporosis by controlling TCF4, and methylation modification of TCF4 can also affect the pathogenesis of osteoporosis.

Analysis of risk factors affecting poor wound healing after primary cleft palate surgery.

OBJECTIVES: To study the risk factors of poor wound healing after primary cleft palate surgery. METHODS: In this study, 980 cases of congenital cleft palate treated by Sommerlad-Furlow in the Department of Cleft Lip and Palate Surgery of Sichuan University from 2017 to 2021 were continuously analyzed. Indicators included patient's age, gender, body weight, cleft palate type, width of the widest fistula, cleft palate index (width of the widest fistula/width at the posterior edge of the maxillary tubercle plane), preoperative white blood cell count, preoperative hemoglobin level, preoperative antibiotic use, doctor's seniority, use of relaxation incision, operation time, postoperative upper respiratory tract infection, and postoperative wound healing. The postoperative wound healing was divided into normal healing, delayed healing, and palatal fistula. Both delayed healing and palatal fistula were classified as poor healing. The factors that may affect the healing outcome of the palatal wound after primary cleft palate repair were analyzed using SPSS 26.0 software. RESULTS: A total of 825 patients (84.2%) had normal healing, 112 patients (11.4%) had delayed hea-ling, and 43 patients (4.4%) had palatal fistula. Doctor's seniority, width of the widest fissure, cleft palate index, and operation time influenced the wound healing effect after cleft palate surgery (P<0.05). Doctors with low seniority, wide width of the widest fistula, large cleft palate index, and long operation time were the risk factors of poor wound healing. CONCLUSIONS: Doctor's seniority, width of the widest fissure, cleft palate index, and operation time are related to the effect of healing effect after cleft palate surgery.

Evaluating the learning curve of high intensity focus ultrasound for breast fibroadenoma by CUSUM analysis: a multi-center study.

OBJECTIVE: To explore the learning curve of high intensity focus ultrasound (HIFU) treatment for breast fibroadenoma. METHODS: A database of 110 patients with 255 breast fibroadenomas who underwent HIFU treatment at two different clinical centers (Center 1 and 2) were retrospectively analyzed. The learning curves of HIFU treatment for breast fibroadenoma were drawn by CUSUM analysis in two centers, respectively. According to the inflection point of the learning curves, the treatment was divided into two groups: initial phase and consolidation phase. HIFU treatment parameters were compared between two groups. The effectiveness and safety results were also evaluated. RESULTS: The inflection points of the learning curves were the 60th treatment in Center 1 and the 65th treatment in Center 2. The screening time, treatment time, sonication time and hyperechoic scale change time were significantly shorter in consolidation phase than those in initial phase of the two centers (p < 0.05). There were no differences in non-perfused volume (NPV) ratio and energy effect factor (EEF) between the two groups in Center 1, while in Center 2, these above-mentioned results in consolidation phase led to a greater improvement than those in initial phase. There was no difference of Visual Analogue Scale (VAS) scores and no adverse event observed in both centers. CONCLUSION: HIFU treatment for breast fibroadenoma was effective and safe. The learning curve of HIFU treatment for breast fibroadenoma can be completed after treating 60-65 tumors without increasing the safety risk.

A treatment algorithm for secondary cleft palate repair based on age and preoperative velopharyngeal closure ratio.

This study aimed to find a surgical treatment algorithm for secondary velopharyngeal insufficiency (VPI), with Furlow palatoplasty or posterior pharyngeal flap (PPF), balancing speaking and breathing. Non-syndromic cleft palate patients with secondary VPI who underwent Furlow palatoplasty or PPF were reviewed. A multinomial logistic regression model was employed to estimate the association between preoperative variables and surgical outcomes. A series of multinomial logistic regression models was utilized to determine the cut-off value of the significant predictors for subgroup comparison. In total, 203 patients were enrolled, with 73 receiving Furlow palatoplasty and 130 receiving PPF. The surgical outcomes of the two techniques were significantly different (p = 0.005). Age was a significant predictor in all intragroup comparative analyses. Preoperative VCR was associated with postoperative velopharyngeal function in patients undergoing Furlow palatoplasty (p = 0.042). The best cut-off values were an age of 13 years and a VCR of 70%. Surgical outcomes in both group B (age <13, VCR <70%; p = 0.017) and group C (age ≥13, VCR ≥70%; p = 0.003) differed significantly between the two surgical techniques. Within the limitations of the study, it is seems that in patients aging <13 years and with a VCR of ≥70%, Furlow palatoplasty should be preferred whenever appropriate to receive adequate velopharyngeal function.

The complete chloroplast genome of Camellia confuse Craib 1914, an economically valuable oil crop.

Camellia confuse Craib 1914 is an industrially valuable oil crop from southern China for which little genetic information is available. Here, we found that its complete chloroplast genome is a circular sequence (156,905 bp) with a large single-copy region (LSC) of 67,724 bp, a small single copy region (SSC) of 18,400 bp, and two inverted repeats (IRs). In total, 130 genes were identified, including 86 protein-coding genes, 36 transfer RNAs, and 8 rRNA genes. Phylogenetic analysis showed that C. confusa is close to C. meiocarpa. These results provide valuable information for accelerating research on the evolution of camellias.