Integrating serum pharmacochemistry, network pharmacology and untargeted metabolomics strategies to reveal the material basis and mechanism of action of Feining keli in the treatment of chronic bronchitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Feining keli (FNKL) is herbal preparation mainly made from Senecio cannabifolius Less., In recent years, more and more studies have found that FNKL has excellent therapeutic effects on chronic bronchitis (CB). Nevertheless, its pharmacodynamic material basis and mechanism of action are still unknown. AIM OF THE STUDY: This study aimed to explore the pharmacodynamic material basis and mechanism of action of FNKL in treating CB. MATERIALS AND METHODS: The CB rat model was induced using nasal drops of lipopolysaccharide (LPS) in combination with smoking. Various assessments including behavioral and body mass examination, lung index measurement, enzyme linked immunosorbent assay (ELISA), as well as histological analyses using hematoxylin and eosin (H&E) and Masson staining were conducted to validate the reliability of the CB model. The serum components of FNKL in CB rats were identified using ultra-high-performance liquid chromatography Orbitrap Exploris mass spectrometer (UHPLC-OE-MS). Network pharmacology was used to predict the network of action of the active ingredients in FNKL based on these serum components. Signaling pathways were enriched and analyzed, and molecular docking was conducted for key targets. Molecular dynamics simulations were performed using GROMACS software. The mechanism was confirmed through a series of experiments including Western blot (WB), immunofluorescence (IF), and reverse transcription (RT)-PCR. Additionally, untargeted metabolomics was employed to identify biomarkers and relevant metabolic pathways associated with the treatment of CB with FNKL. RESULTS: In CB rats, FNKL improved body mass, lung index, and pathological damage of lung tissues. It also decreased interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), malonaldehyde (MDA) levels, and percentage of lung collagen fiber area. Furthermore, FNKL increased IL-10 and superoxide dismutase (SOD) levels, which helped alleviate bronchial inflammation in the lungs. A total of 70 FNKL chemical components were identified in CB rat serum. Through network pharmacology analysis, 5 targets, such as PI3K, AKT, NF-κB, HIF-1α, and MYD88, were identified as key targets of FNKL in the treatment of CB. Additionally, the key signaling pathways identified were PI3K/AKT pathway、NF-κB/MyD88 pathway、HIF-1α pathway. WB, IF, and RT-PCR experiments were conducted to confirm the findings. Molecular docking studies demonstrated successful docking of 16 potential active components with 5 key targets. Additionally, molecular dynamics simulations indicated the stability of quercetin-3-galactoside and HIF-1α. Metabolomics analysis revealed that FNKL primarily regulated pathways related to alpha-linolenic acid metabolism, primary bile acid biosynthesis, bile secretion, arachidonic acid metabolism, neuroactive ligand-receptor interaction, and folate biosynthesis. Furthermore, the expression levels of traumatic acid, traumatin, alpha linolenic acid, cholic acid, 2-arachidonoylglycerol, deoxycholic acid, 7,8-dihydroneopterin, and other metabolites were found to be regulated. CONCLUSION: FNKL exhibits positive therapeutic effects on CB, with quercetin-3-galactoside identified as a key active component. The mechanism of FNKL's therapeutic action on CB involves reducing inflammatory response, oxidative stress, and regulating metabolism, and its molecular mechanism was better elucidated in a holistic manner. This study serves as a reference for understanding the pharmacodynamic material basis and mechanism of action of FNKL in treating CB, and provides avenues for exploring the effects of compounded herbal medicines on CB.

Characteristics of astigmatism in school-age children aged 5 to 13 years in northeast Sichuan: a cross-sectional school-based study.

Background: Astigmatism is closely associated with myopia progression, vision loss, eye fatigue and amblyopia, which seriously endangers children's eye health. This study aims to investigate the prevalence and characteristic distribution of astigmatism in children in Langzhong City, providing valuable insights for allocating resources and develop prevention and control strategies. Methods: A cross-sectional study and random sampling survey were conducted. Between January and November 2021, 21,415 students aged 5 to 13 years from 14 primary schools in Langzhong City underwent non-cycloplegic refractive testing using autorefraction. The data on myopia were analyzed using SPSS (Statistical Package for the Social Sciences) version 23.0. Results: The inclusion criterion was set at an absolute astigmatism value of ≥0.50D. Among the 21,415 children studied, 61.70% were found to have astigmatism. The prevalence of astigmatism varied significantly across different grades (χ2=501.414, P<0.001). The predominant types of astigmatism were mild astigmatism (0.50-1.00D) and with-the-rule astigmatism. Mixed astigmatism was primarily observed in children in grades 1 and 2, while compound myopic astigmatism was more common in children in grades 3 to 6. These differences were statistically significant. As the degree of astigmatism increased, the proportions of against-the-rule astigmatism, oblique astigmatism, compound myopic astigmatism, and simple hyperopic astigmatism decreased, whereas the proportions of with-the-rule astigmatism, mixed astigmatism, and compound hyperopic astigmatism increased. Conclusions: The prevalence of astigmatism among school-age children aged 5 to 13 years in northeast Sichuan is notably high, with compound myopic astigmatism and with-the-rule astigmatism being the most common types. Regular refractive examinations are crucial for the early detection and management of astigmatism.

Ultrasound and diffuse optical tomography-transformer model for assessing pathological complete response to neoadjuvant chemotherapy in breast cancer.

Significance: We evaluate the efficiency of integrating ultrasound (US) and diffuse optical tomography (DOT) images for predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients. The ultrasound-diffuse optical tomography (USDOT)-Transformer model represents a significant step toward accurate prediction of pCR, which is critical for personalized treatment planning. Aim: We aim to develop and assess the performance of the USDOT-Transformer model, which combines US and DOT images with tumor receptor biomarkers to predict the pCR of breast cancer patients under NAC. Approach: We developed the USDOT-Transformer model using a dual-input transformer to process co-registered US and DOT images along with tumor receptor biomarkers. Our dataset comprised imaging data from 60 patients at multiple time points during their chemotherapy treatment. We used fivefold cross-validation to assess the model's performance, comparing its results against a single modality of US or DOT. Results: The USDOT-Transformer model demonstrated excellent predictive performance, with a mean area under the receiving characteristic curve of 0.96 (95%CI: 0.93 to 0.99) across the fivefold cross-validation. The integration of US and DOT images significantly enhanced the model's ability to predict pCR, outperforming models that relied on a single imaging modality (0.87 for US and 0.82 for DOT). This performance indicates the potential of advanced deep learning techniques and multimodal imaging data for improving the accuracy (ACC) of pCR prediction. Conclusion: The USDOT-Transformer model offers a promising non-invasive approach for predicting pCR to NAC in breast cancer patients. By leveraging the structural and functional information from US and DOT images, the model offers a faster and more reliable tool for personalized treatment planning. Future work will focus on expanding the dataset and refining the model to further improve its accuracy and generalizability.

The Main Failure Modes of Hot-Work Die Steel and the Development Status of Traditional Strengthening Methods and Nano-Strengthening Technology.

As an important part of die steels, hot-work die steels are mainly used to manufacture molds made of solid metal or high-temperature liquid metal from heating to recrystallization temperature. In view of the requirements for mechanical properties and service life for hot-work die steel, it is conducive to improve the thermal fatigue resistance, wear resistance, and oxidation resistance of hot work die steel. In this review, the main failure modes of hot-work die steel were analyzed. Four traditional methods of strengthening and toughening die steel were summarized, including optimizing alloying elements, electroslag remelting, increasing the forging ratio, and heat treatment process enhancement. A new nano-strengthening method was introduced that aimed to refine the microstructure of hot-work abrasive steel and improve its service performance by adding nanoparticles into molten steel to achieve uniform dispersion. This review provides an overview to improve the service performance and service life of hot work die steel.

Establishment and Validation of a Risk Prediction Model for Non-Invasive Ventilation Failure After Birth in Premature Infants with Gestational Age < 32 Weeks.

OBJECTIVES: This study was performed to construct and validate a risk prediction model for non-invasive ventilation (NIV) failure after birth in premature infants with gestational age < 32 weeks. METHODS: The data were derived from the multicenter retrospective study program - Jiangsu Provincial Neonatal Respiratory Failure Collaboration Network from Jan 2019 to Dec 2021. The subjects finally included were preterm infants using NIV after birth with gestational age less than 32 weeks and admission age within 72 h. After screening by inclusion and exclusion criteria, 1436 babies were subsequently recruited in the study, including 1235 infants in the successful NIV group and 201 infants in the failed NIV group. RESULTS: (1) Gestational age, 5 min Apgar, Max FiO2 during NIV, and FiO2 fluctuation value during NIV were selected by univariate and multivariate analysis. (2) The area under the curve of the prediction model was 0.807 (95% CI: 0.767-0.847) in the training set and 0.825 (95% CI: 0.766-0.883) in the test set. The calibration curve showed good agreement between the predicted probability and the actual observed probability (Mean absolute error = 0.008 for the training set; Mean absolute error = 0.012 for the test set). Decision curve analysis showed good clinical validity of the risk model in the training and test cohorts. CONCLUSION: This model performed well on dimensions of discrimination, calibration, and clinical validity. This model can serve as a useful tool for neonatologists to predict whether premature infants will experience NIV failure after birth.

NIR Light and GSH Dual-Responsive Upconversion Nanoparticles Loaded with Multifunctional Platinum(IV) Prodrug and RGD Peptide for Precise Cancer Therapy.

Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of drug delivery, with the aim to promote bioavailability and minimize side effects. Herein, a multitargeting octahedral platinum(IV) prodrug with octadecyl aliphatic chain and histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions to improve the therapeutic effect of cisplatin was loaded on the upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment of DSPE-PEG2000 and arginine-glycine-aspartic (RGD) peptide endowed the nanovehicles with high biocompatibility and tumor specificity. The fabricated nanoparticles (UCNP/Pt(IV)-RGD) can be triggered by upconversion luminescence (UCL) irradiation and glutathione (GSH) reduction to controllably release Pt(II) species and PHB, inducing profound cytotoxicity. Both in vitro and in vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, high tumor-targeting specificity, and real-time UCL imaging capacity, presenting an intelligent platinum(IV) prodrug-loaded nanovehicle for UCL-guided dual-stimuli-responsive combination therapy.

Cattle hair as a bioindicator for short- and medium-chain chlorinated paraffin monitoring on cattle farms.

Short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) are hazardous industrial chemicals that tend to bioaccumulate in animal-derived foodstuffs through the food supply chain. However, the lack of reliable noninvasive bioindicators hinders the monitoring of farm animal exposure to CPs. In this study, 169 cattle hair samples were collected from beef cattle farms in six Chinese provinces, with further beef, feed, and soil samples being collected in Hebei province. Geographical differences in CP concentrations were observed in the hair samples, and CP concentrations in samples collected from Hebei province decreased in the following order: hair > feed > beef > soil. C10-11Cl6-7 and C14Cl7-8 were the predominant SCCPs and MCCPs, respectively, in all the hair, beef, feed, and soil samples. CP concentrations in hair samples significantly correlated with those in beef, feed, and soil samples, indicating that hair can be used as a bioindicator of cattle exposure to CPs. The possible health risks associated with exposure to CPs through beef consumption, especially for children and high-volume beef consumers, should be further investigated.

Association between previous consumption of sugar-sweetened beverages and diabetes remission in patients with newly diagnosed type 2 diabetic ketoacidosis.

This study examined the potential correlation between the immoderate intake of sugar-sweetened beverages (SSBs) and the subsequent rate of diabetes remission (DR). 206 individuals who met the eligibility criteria between January 2019 and June 2022 were recruited. Inquiries were conducted to gather information on the participants' beverage consumption before the onset. Subsequently, the participants were separated into the diabetes remission group (DR group) and nondiabetes remission group (NDR group) depending on whether they met the diagnostic criteria for diabetes remission. Baseline clinical elements within the two groups were juxtaposed, and factors influencing diabetes remission were identified through logistic regression analyses. The cutoff values of each critical factor were determined based on the receiver operating characteristic curve. One hundred and nine patients reported a history of SSB consumption, while the remaining 58 reported no such history. After 1 year, 40 patients achieved remission from diabetes. Compared with the NDR group, a higher SSBs ratio, body mass index (BMI), and blood creatinine (BCr) was observed in the DR group after adjusting for confounders, SSBs (odds ratio [OR] = 3.503; 95% confidence interval [CI] = 1.334-9.202; p = 0.011) and BCr (OR = 1.038; 95% CI = 1.003-1.079; p = 0.042) emerged as independent predictors of DR. The composite index of SSBs and BCr efficaciously predicted DR (area under the ROC curve [AUC] = 0.810, p < 0.001). SSBs and BCr were independent risk factors for DR. The amalgamation of these markers could more accurately predict DR.

HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis.

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-ß1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV-HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-ß1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-ß1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.

Intubation at Birth Is Associated with Death after Pulmonary Hemorrhage in Very Low Birth Weight Infants.

OBJECTIVE: This retrospective cohort study was performed to clarify the association between intubation in the delivery room and the mortality after pulmonary hemorrhage in very low birth weight infants (VLBWIs) during hospitalization. METHODS: The study participants were screened from the VLBWIs admitted to the neonatal intensive care unit (NICU) of the Children's Hospital Affiliated to Nanjing Medical University from 31 July 2019 to 31 July 2022. The newborns who ultimately were included were those infants who survived until pulmonary hemorrhage was diagnosed. These subjects were divided into the intubation-at-birth group (n = 29) and the non-intubation-at-birth group (n = 35), retrospectively. RESULTS: Univariate analysis found that the intubation group had a higher mortality and shorter hospital stay than the non-intubation group (p < 0.05) (for mortality: 25/29 (86.21%) in intubation group versus 14/35 (40.00%) in non-intubation group). By multivariate analysis, the result further showed that intubation in the delivery room was related to shorter survival time and higher risk of death (adjusted hazard ratio: 2.341, 95% confidence interval: 1.094-5.009). CONCLUSIONS: Intubation at birth suggested a higher mortality in the VLBWIs when pulmonary hemorrhage occurred in the NICU.

Ultrasonic-assisted extraction of polysaccharide from Paeoniae Radix alba: Extraction optimization, structural characterization and antioxidant mechanism in vitro.

Paeoniae Radix alba is used in Traditional Chinese Medicine for the treatment of gastrointestinal disorders, immunomodulatory, cancer, and other diseases. In the current study, the yield of Paeoniae Radix alba polysaccharide (PRP) was significantly increased with optimal ultrasound-assisted extraction compared to hot water extraction. Further, an acidic polysaccharide (PRP-AP) was isolated from PRP after chromatographic separation and was characterized as a typical pectic polysaccharide with side chains of arabinogalactans types I and II. Moreover, it showed antioxidant effects on LPS-induced damage on IPEC-J2 cells determined by qRT-PCR and ELISA, including decreasing the pro-inflammatory factors' expressions and increasing the antioxidant enzymes activities, which was shown to be related to the Nrf2/Keap1 pathway modulated by PRP-AP. The metabolites change (such as itaconate, cholesterol sulfate, etc.) detected by untargeted metabolomic analysis in cells was also shown to be modulated by PRP-AP, and these metabolites were further utilized and protected cells damaged by LPS. These results revealed the cellular active mechanism of the macromolecular PRP-AP on protecting cells, and supported the hypothesis that PRP-AP has strong benefits as an alternative dietary supplement for the prevention of intestinal oxidative stress by modulating cellular metabolism.

The application value of metagenomic next-generation sequencing technology in the diagnosis and treatment of neonatal infectious meningitis - a single center retrospective case-control study.

OBJECTIVE: This retrospective study was conducted to investigate the application value of metagenomics next generation sequencing (mNGS) technology in the diagnosis and treatment of neonatal infectious meningitis. METHODS: From 1 January 2020 to 31 December 2022, 73 newborns suspected of infectious meningitis were hospitalized. After screening by inclusion and exclusion criteria, 69 newborns were subsequently included in the study, containing 27 cases with positive mNGS result and 42 cases with negative mNGS result. Furthermore, according to the diagnosis of meningitis, mNGS positive group and mNGS negative group were further divided into infectious meningitis with mNGS (+) group (n = 27) and infectious meningitis with mNGS (-) group (n = 26), respectively. RESULTS: (1) Compared with cerebrospinal fluid (CSF) culture, mNGS has better diagnostic value [positive predictive value (PPV) = 100.00% (27/27), negative predictive value (NPV) = 38.10% (16/42), agreement rate = 62.32% (43/69), area under the curve (AUC) = 0.750, 95% confidence interval (CI): 0.636-0.864]. (2) There were significant differences in the onset age, age at first CSF test, CSF leukocyte count, CSF glucose, positive rate of CSF culture, blood leukocyte count, procalcitonin (PCT), C-reaction protein (CRP), age at first mNGS test and adjusting anti-infective medication in the comparison between infectious meningitis with mNGS (+) group and infectious meningitis with mNGS (-) group (p < 0.05). (3) mNGS could help improve the cure rate [crude odds ratio (OR) = 3.393, 95%CI: 1.072-10.737; adjusted OR = 15.580, 95%CI: 2.114-114.798]. CONCLUSION: Compared with classic meningitis detection methods, mNGS has better PPV, NPV, agreement rate, and AUC. mNGS could help improve the cure rate.

Sirolimus combined with glucocorticoids in the treatment of Kasabach-Merritt phenomenon in a neonate: A case report.

RATIONALE: Kaposiform hemangioendothelioma is an aggressive vascular tumor that is often associated with life-threatening coagulopathies and Kasabach-Merritt phenomenon. Pathologic biopsies can provide a good basis for diagnosis and treatment. Therapy with srolimus combined with glucocorticoids may offer patients a favorable prognosis. PATIENT CONCERNS: A large purplish-red mass on the knee of a child with extremely progressive thrombocytopenia and refractory coagulation abnormalities. Conventional doses of glucocorticoids alone failed to improve coagulation abnormalities and the child developed large cutaneous petechiae and scalp hematomas. DIAGNOSIS: Kaposiform hemangioendothelioma combined with Kasabach-Merritt phenomenon. INTERVENTIONS: The patient received prednisolone 2.0 mg/kg*d for 4 days. Blood products were transfused to ensure vital signs and to complete the pathologic biopsy. Sirolimus combined with prednisolone was given after clarifying the diagnosis of Kaposiform hemangioendothelioma. OUTCOMES: The tumor basically disappeared on examination and the ultrasound showed a subcutaneous hyperechoic mass with normal blood flow. LESSONS: Sirolimus combined with glucocorticoids is effective in controlling Kasabach-Merritt phenomenon and pathologic biopsy is important for definitive diagnosis.

Bee colonies map the short- and medium-chain chlorinated paraffin contamination from the apiary environment.

Chlorinated paraffins (CPs) are industrial chemicals that have potential adverse effects in the environment and on human health. This study investigated CPs in apiary environment, honeybees, and bee products from two rural areas of Beijing, China. The median concentrations of short-chain CPs (SCCPs) and medium-chain CPs (MCCPs) were 22 and 1.6 ng/m3 in the ambient air, 1350 and 708 ng/g dry mass (dw) in bees, 1050 and 427 ng/g dw in flowers, 37 and 54 ng/g in honey, 78 and 53 ng/g dw in bee pollen, 36 and 30 ng/g dw in soil, and 293 and 319 ng/g dw in bee wax. C10Cl6-7 and C14Cl7-8 dominated SCCPs and MCCPs in these samples, respectively. The concentrations and distributions of CPs in samples from apiaries located in the two regions varied. Long-range transportation of air masses was identified as an important source of CPs in apiaries. A close relationship between CPs in bees and the apiary environment indicated that bees could act as bioindicators for CP contamination in the environment. A human health risk assessment found that there were low risks for adults and children exposed to CPs through consumption of honey and pollen from the studied regions.

PA-NeRF, a neural radiance field model for 3D photoacoustic tomography reconstruction from limited Bscan data.

We introduce a novel deep-learning-based photoacoustic tomography method called Photoacoustic Tomography Neural Radiance Field (PA-NeRF) for reconstructing 3D volumetric PAT images from limited 2D Bscan data. In conventional 3D volumetric imaging, a 3D reconstruction requires transducer element data obtained from all directions. Our model employs a NeRF-based PAT 3D reconstruction method, which learns the relationship between transducer element positions and the corresponding 3D imaging. Compared with convolution-based deep-learning models, such as Unet and TransUnet, PA-NeRF does not learn the interpolation process but rather gains insight from 3D photoacoustic imaging principles. Additionally, we introduce a forward loss that improves the reconstruction quality. Both simulation and phantom studies validate the performance of PA-NeRF. Further, we apply the PA-NeRF model to clinical examples to demonstrate its feasibility. To the best of our knowledge, PA-NeRF is the first method in photoacoustic tomography to successfully reconstruct a 3D volume from sparse Bscan data.

Erbium: YAG laser treatment efficacy and association with histologic features for giant congenital melanocytic nevi management.

BACKGROUND: Limited research exists on laser treatment of giant congenital melanocytic nevus (GCMN). OBJECTIVE: We sought to elucidate the efficacy of the Erbium: YAG laser on GCMN and the histologic factors associated with a positive clinical response. METHODS AND MATERIALS: Between 2019 and 2022, we enrolled 30 medium-to-giant CMN patients who underwent Er: YAG laser treatment. All patients received biopsies before and after laser treatments. Clinical efficacy outcomes were evaluated by the investigator's global assessment (IGA), 5-point scale of depigmentation, and Vancouver Scar Scale (VSS) scores at least 6 months after treatment. RESULTS: Of the 30 cases, 18 (60.0%) showed improvement (IGA score ≥3). Eight (26.7%) patients showed repigmentation. Eight (26.7%) patients developed hypertrophic scars. The average IGA, depigmentation, and VSS scores were 2.93, 3.57, and 3.20. The IGA score was higher (3.24 ± 1.18 vs. 2.22 ± 0.97, p = 0.031) and a lower repigmentation rate (14.3% vs. 55.6%, p = 0.032) was observed in the cases with Grenz zone. The IGA score was higher (3.33 ± 1.24 vs. 2.13 ± 0.89, p = 0.023) and the repigmentation rate was lower (11.1% vs. 50.0%, p = 0.034) also in the cases with the melanocytes nests with aggregation of melanin. Lesions with superficial ablation resulted in less hypertrophic scar formation than those with deep ablation (5.9% vs. 53.8%, p < 0.05). CONCLUSION: The Er: YAG laser demonstrated effective clinical results for GCMNs. The grenz zone and the melanocytes nests with aggregation of melanin are promising predictors of laser efficacy.

Global fungal-host interactome mapping identifies host targets of candidalysin.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.

Historical and contemporary management of infantile hemangiomas: a single-center experience.

Objective: This study explores the 22-year evolution of Infantile Hemangiomas (IHs) treatment strategies at a single-center hospital, aiming to establish an individualized IHs management protocol. Methods: Retrospective review of IHs infants 2000-2022 at the Department of Plastic Surgery, Jiangxi Provincial Children's Hospital. Results: In our study of 27,513 IHs cases, 72.2% were female, with the median age at first hospital visit being 25 days. The majority of cases had localized and superficial lesions primarily on the head, face, and neck (67.5%). Ulceration rates fell from 21.1% to 12.6% with the introduction of propranolol. Management strategies have shifted over time, with the proportion of cases undergoing expectant management dropping from 32.9% to 12.4%. Since 2008, 26.1% of patients were treated with oral propranolol, largely replacing corticosteroids. Topical ß-blockers have been used in 12.1% of cases, leading to a reduction in local injection therapy from 20.8% to 13.2%. Laser therapy, introduced in 2016, has been used in 13.8% of cases, while surgical excision has dropped from 25.0% to 8.5% due to alternative treatment options. Combination therapy was used in 8.8% of cases post-2015, indicating a rising trend. Drawing from the evolution of IHs management strategies, an individualized protocol for the management of IHs was successfully established. Conclusion: Treatment for IHs has evolved over recent decades, with less invasive medical interventions increasingly replacing more invasive methods. Furthermore, a personalized treatment protocol established in this study could boost the cure rate of IHs while minimizing potential side effects and complications.