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Objective: People suffering from coronavirus disease 2019 (COVID-19) are prone to develop pulmonary fibrosis (PF), but there is currently no definitive treatment for COVID-19/PF co-occurrence. Kaempferol with promising antiviral and anti-fibrotic effects is expected to become a potential treatment for COVID-19 and PF comorbidities. Therefore, this study explored the targets and molecular mechanisms of kaempferol against COVID-19/PF co-occurrence by bioinformatics and network pharmacology. Methods: Various open-source databases and Venn Diagram tool were applied to confirm the targets of kaempferol against COVID-19/PF co-occurrence. Protein-protein interaction (PPI), MCODE, key transcription factors, tissue-specific enrichment, molecular docking, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to clarify the influential molecular mechanisms of kaempferol against COVID-19 and PF comorbidities. Results: 290 targets and 203 transcription factors of kaempferol against COVID-19/PF co-occurrence were captured. Epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase SRC (SRC), mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 8 (MAPK8), RAC-alpha serine/threonine-protein kinase (AKT1), transcription factor p65 (RELA) and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) were identified as the most critical targets, and kaempferol showed effective binding activities with the above critical eight targets. Further, anti-COVID-19/PF co-occurrence effects of kaempferol were associated with the regulation of inflammation, oxidative stress, immunity, virus infection, cell growth process and metabolism. EGFR, interleukin 17 (IL-17), tumor necrosis factor (TNF), hypoxia inducible factor 1 (HIF-1), phosphoinositide 3-kinase/AKT serine/threonine kinase (PI3K/AKT) and Toll-like receptor signaling pathways were identified as the key anti-COVID-19/PF co-occurrence pathways. Conclusion: Kaempferol is a candidate treatment for COVID-19/PF co-occurrence. The underlying mechanisms may be related to the regulation of critical targets (EGFR, SRC, MAPK3, MAPK1, MAPK8, AKT1, RELA, PIK3CA and so on) and EGFR, IL-17, TNF, HIF-1, PI3K/AKT and Toll-like receptor signaling pathways. This study contributes to guiding development of new drugs for COVID-19 and PF comorbidities.

Ocular diseases associated with retinal ganglion cell (RGC) degeneration is the most common neurodegenerative disorder that causes irreversible blindness worldwide. It is characterized by visual field defects and progressive optic nerve atrophy. The underlying pathophysiology and mechanisms of RGC degeneration in several ocular diseases remain largely unknown. RGCs are a population of central nervous system neurons, with their soma located in the retina and long axons that extend through the optic nerve to form distal terminals and connections in the brain. Because of this unique cytoarchitecture and highly compartmentalized energy demand, RGCs are highly mitochondrial-dependent for adenosine triphosphate (ATP) production. Recently, oxidative stress and mitochondrial dysfunction have been found to be the principal mechanisms in RGC degeneration as well as in other neurodegenerative disorders. Here, we review the role of oxidative stress in several ocular diseases associated with RGC degenerations, including glaucoma, hereditary optic atrophy, inflammatory optic neuritis, ischemic optic neuropathy, traumatic optic neuropathy, and drug toxicity. We also review experimental approaches using cell and animal models for research on the underlying mechanisms of RGC degeneration. Lastly, we discuss the application of antioxidants as a potential future therapy for the ocular diseases associated with RGC degenerations.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO‐related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO‐related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α‐ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo . This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO‐chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO‐related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function. Synopsis Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death and ameliorate visual impairment in the clinic. DFO primarily acts on RPE and disrupts its iron homeostasis, causing atrophic lesions. DFO upregulates HIF2α and undermines mitochondrial oxidative phosphorylation in the RPE, accounting for its susceptibility to iron depletion. RPE intolerance to HIF2α‐induced anaerobic glycolysis contributes to susceptibility to DFO toxicity. RPE survival is sustained by mitochondrial oxidative phosphorylation. The glycolytic photoreceptor is initially spared from the DFO‐enhanced HIF levels. AKG, an intermediary metabolite of the Krebs cycle, destabilizes HIF2α and preserves mitochondrial respiration capacity, which protect RPE from damage and mitigates visual impairment in the clinic. Graphical Abstract Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death, and ameliorate visual impairment in the clinic.

Diabetic ketoacidosis (DKA) is the most common acute complication in people with diabetes. We aimed to assess the association of DKA with the risk of diabetic retinopathy (DR) and related ophthalmic interventions in individuals with type 2 diabetes (T2D). To ensure similar T2D management and severity at baseline between groups, we enrolled 1,007 T2D patients with and without DKA matched by anti-diabetic combination within the initial 3 months of diabetes diagnosis, gender, birth and diabetes diagnosis year in Taiwan National Health Insurance Research Database from 2000 to 2019. We employed Fine and Gray competing risk model to assess the risk of non-proliferative DR (NPDR), proliferative DR (PDR) and panretinal photocoagulation (PRP). Our results showed that patients with DKA had an increased risk of DR (adjusted subdistribution hazard ratio [SHR] 1.64 [95% CI, 1.34–2.01]) and PRP (SHR 1.43 [1.11–1.86]). The risk of NPDR is elevated when diabetes-to-DKA duration exceeded 24 months (SHR 2.15 [1.52–3.05]), while 1–24 months duration increased PDR risk (SHR 3.72 [1.76–7.88]). Patients with DKA onset at ages 46–55 and 56–65 showed specific PDR (SHR 1.82 [0.99–3.33]) and NPDR susceptibilities (SHR 6.52 [2.30–18.49]), respectively. Our study showed that DKA was associated with a higher risk of developing DR and requiring related ophthalmic interventions compared to a matched cohort with similar T2D baseline characteristics.

Objective This study aimed to evaluate the clinical effect of transcutaneous pelvic floor magnetic stimulation combined with urination training in the treatment of overactive bladder (OAB) in children. Methods In this study, the clinical data of 42 children with OAB who were treated with transcutaneous pelvic floor magnetic stimulation combined with the urination training method at our hospital from March 2022 to December 2022 (Group B) were collected. The clinical data of 50 children with OAB who were treated with the urination training method at our hospital from December 2021 to February 2022 (Group A) were used as controls. The clinical efficacy of treatment was compared between the two groups. Results After 2 weeks of treatment, the Akbal scale scores of the two groups were significantly lower than those before treatment ( P  < 0.05). After two weeks of treatment, the Akbal score of Group B was significantly lower than that of Group A ( P  < 0.05). The maximum voiding volume (MVV), average voiding volume (AVV), maximum urinary flow rate, average urinary flow rate and voiding frequency significantly differed between the two groups as well as before and after treatment ( P  < 0.05). Specifically, the MVV, AVV and maximum urinary flow rate, average urinary flow rate and voiding frequency significantly differed between the two groups after treatment, and the improvement value of Group B was greater than that of Group A ( P  < 0.05). After 2 weeks of treatment, the Akbal score revealed that the degree of improvement in frequent urination throughout the day, the degree of urgency and quality of life of patients in Group B were significantly greater than those in Group A ( P  < 0.05). Conclusion Transcutaneous pelvic floor magnetic stimulation combined with urination training was effective in the treatment of children with OAB. Compared with urination training alone, this method can achieve better therapeutic effects and can more effectively improve the symptoms, bladder capacity and urination function of children after 2 weeks of treatment.

Discordance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer, metastatic lesion and synchronous axillary lymph node metastasis has been reported in the series studies. Systemic treatment of primary invasive breast cancer patients with synchronous axillary metastasis is currently based on the biomarker characteristics of the primary tumor; however, hormone receptors and HER2 status may change throughout tumor progression from the primary tumor to the synchronous axillary metastasis. As local metastasis, the synchronous axillary lymph node metastasis may represent the potentially metastatic breast cancer cells much better than the primary tumor. Hence, the determination of hormone receptors and HER2 status should be routinely performed in synchronous axillary nodal metastasis, together with primary tumor, to guide therapy management and evaluate the recurrent risk of primary invasive breast cancer patients with synchronous axillary nodal metastasis, which may even change the postoperative risk categories (St. Gallen consensus) of breast cancer in these patients. This article will review the studies on the discordance and clinical significance of ER, PR, and HER2 receptor status between primary breast cancer and synchronous axillary lymph node metastasis.

Background：Core fucosylation （CF）,catalyzed by α-1,6 fucosyltransferase （Fut8） in mammals,plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins,including transforming growth factor （TGF）-β receptors and platelet-derived growth factor （PDGF） receptors.However,its effect on peritoneal fibrosis is unknown.Here,we investigated its influence on epithelial-mesenchymal transition （EMT） of rat peritoneal mesothelial cells （PMCs） in vitro induced by a high-glucose （HG） culture solution.Methods：Rat PMCs were first cultured in a HG （2.5%） culture solution to observe the CF expression level （fluorescein isothiocyanate-lens culinaris agglutinin）,we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA （siRNA） to observe whether inhibiting CF decreases the messenger RNA （mRNA） expression and protein expression of Fut8 and reverses EMT status.Rat PMCs were randomly divided into control group,mock group （transfected with scrambled siRNA）,Fut8 siRNA group,HG group,HG ＋ mock group,and HG ＋ Fut8 siRNA group.Finally,we examined the activation of TGF-β/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase （ERK） signaling to observe the influence of CF on them.Results：CF,Fut8 mRNA,and protein expression were all significantly upregulated in HG-induced EMT model than those in the control rat PMCs （P 〈 0.05）.Fut8 siRNA successfully blocked CF of TGF-β receptors and PDGF receptors and attenuated the EMT status （E-cadherin and α-SMA and phenotypic changes） in HG-induced rat PMCs.In TGF-β/Smad2/3 signaling,Fut8 siRNA did not suppress the protein expression of TGF-3 receptors and Smad2/3;however,it significantly suppressed the phosphowlation of Smad2/3 （relative expression folds of HG ＋ Fut8 group vs.HG group：7.6 ± 0.4 vs.15.1 ± 0.6,respectively,P 〈 0.05）.In PDGF/ERK signaling,Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK,but it significantly suppressed the phosphorylation of ERK （relative expression folds of HG ＋ Fut8 group vs.HG group：8.7 ± 0.9 vs.15.6 ± 1.2,respectively,P 〈 0.05）.Blocking CF inactivated the activities of TGF-β and PDGF signaling pathways,and subsequently blocked EMT.Conclusions：These results demonstrate that CF contributes to rat PMC EMT.and that blocking it attenuates EMT.CF regulation is a potential therapeutic target of peritoneal fibrosis.

This study is to estimate the status and comparison of glucose intolerance in female breast cancer patients at initial diagnosis and during chemotherapy through an oral glucose tolerance test (OGTT), as well as to learn the effect of chemotherapy on the glucose metabolism of breast cancer patients. All the 79 breast cancer patients at initial diagnosis, with the mean age of 53.2 years, and 96 breast cancer patients before the 5th or 6th cycle of chemotherapy, with the mean age of 51.5 years, participated in the study from December 2012 to October 2013. After an overnight fast, participants underwent OGTT test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) in them. Previously diagnosed diabetes among the female breast cancer patients was determined on the self-report and the medical record. The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5% (p<0.05), 50.6% and 28.1% (p<0.05), and 25.3% and 33.3% (p>0.05), respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT. Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.

The components of EAM are strongly correlated with LOD and play an important role in UT1-UTC and LOD prediction. However, the EAM dataset is prone to be noisy. In this study, we propose a hybrid method to reduce the noise of the EAM data and improve the accuracy of UT1-UTC and LOD predictions. We use the EOP data to denoise the EAM data, and use Kalman filtering to denoise the 1–6 days forecast of EAM. Then, we use the denoised EAM dataset to improve the UT1-UTC and LOD prediction. The denoised EAM dataset improved the prediction of UT1-UTC within 10 days by 20%. In addition, we found that by introducing two additional periodic (23.9 days and 91.3 days) components for the least-squares fitting, the accuracy of UT1-UTC and LOD prediction in the range of 30–80 days is significantly improved. In more than 430 UT1-UTC and LOD prediction experiments conducted during 2021–2022, the improvements in the 1–6 days forecast were significant. For the 6th day, 30th day, and 60th day, the MAE of UT1-UTC was 0.1592, 2.9169, and 6.7857 ms, respectively, corresponding to improvements of 31.35, 12.60, and 12.93%, respectively, when compared to predictions of Bulletin A. The MAE of LOD predictions on the 1st day, 6th day, 30th day, and 90th day was 0.0255, 0.0432, 0.1694, and 0.2505 ms, respectively, which improved by 26.09, 14.29, 6.36, and 3.76% when compared with our second EOPPCC method.

Given that effective angular momentum (EAM) data demonstrate a strong correlation with length of day (LOD) data and are extensively utilized in the prediction of the universal time (UT1), this research integrated the EAM into the design of a Kalman filter. At the solution combination level, the UT1, LOD, and EAM were merged to derive a UT1/LOD sequence featuring higher accuracy and enhanced continuity. To begin with, a comprehensive evaluation of the three datasets was conducted to identify the systematic biases and periodic components of the LOD. Subsequently, geodetic angular momentum (GAM) data were employed to rectify the EAM data spanning from 2019 to 2022. Finally, the corrected EAM was combined with the UT1 and LOD through Kalman modeling. To evaluate the capability of this EAM-aided Kalman filter, Jet Propulsion Laboratory (JPL) and Wuhan University (WHU) LOD data, International Very Long Baseline Interferometry (VLBI) Service for Geodesy and Astrometry (IVS) intensive and National Time Service Center (NTSC) UT1 data, and German Research Centre for Geosciences (GFZ) EAM data were used for combination experiments. The final estimations of the UT1 and LOD were compared with the International Earth Rotation Service (IERS) Earth-orientation parameter (EOP) 20 C04 series. From July to September 2021, the root mean square (RMS) of the combined UT1 series was reduced from 38 µs to 26 µs for the IVS intensive UT1, with an improvement of 30%. The RMS of the combined UT1 series was reduced from 102 µs to 47 µs for the NTSC UT1 measurement, with an improvement of 54%. The bias of the LOD was effectively corrected and the RMS of the LOD improved by 60–70% and the standard deviation of the LOD improved by 11–30%. Further, the final estimated uncertainties of the UT1 and LOD are, in general, consistent with the estimated RMS, indicating a reasonable estimation of uncertainties. Comparative experiments with and without the EAM show that using EAM data can effectively reduce the extreme values, especially for the NTSC UT1 series with large uncertainties. In summary, this EAM-aided Kalman filter can produce UT1 and LOD series with improved accuracy, and with reasonable uncertainties.