BACKGROUND: Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI assistance. METHODS: An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo . We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo . RESULTS: AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis. CONCLUSION AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
Animals ; Glaucoma/metabolism* ; Neuroprotective Agents/pharmacology* ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Artificial Intelligence ; Retinal Ganglion Cells/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Male

This study aimed to introduce a modified Byars staged procedure and investigate its application value in patients with severe hypospadias. We retrospectively analyzed the clinical data of patients with severe hypospadias admitted to the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between October 2012 and October 2022. In total, 31 patients underwent the conventional Byars procedure (conventional group), and 45 patients underwent the modified Byars staged procedure (modified group). Our modified strategy was built upon the standard Byars procedure by incorporating glansplasty during the first stage and employing a Y-shaped flap in conjunction with a glandular tunnel for urethroplasty during the second stage. Notably, there were no statistically significant differences in the preoperative baseline characteristics, duration of surgery, amount of blood loss, or occurrence of postoperative complications, including urethral fistula, stricture and diverticulum, or penile curvature, between the conventional and modified groups. However, there was a significantly lower incidence of coronal sulcus fistula (0 vs 16.1%, P = 0.02) and glans dehiscence (0 vs 12.9%, P = 0.02) in the surgical group than that in the conventional group. In addition, the modified group exhibited a notably greater rate of normotopic urethral opening (100.0% vs 83.9%, P = 0.01) and a higher mean score on the Hypospadias Objective Penile Evaluation (HOPE; mean ± standard error of mean: 8.6 ± 0.2 vs 7.9 ± 0.3, P = 0.02) than did the conventional group. In conclusion, the modified Byars staged procedure significantly reduced the risks of glans dehiscence and coronal sulcus fistula. Consequently, it offers a promising approach for achieving favorable penile esthetics, thereby providing a reliable therapeutic option for severe hypospadias.
Humans ; Hypospadias/surgery* ; Male ; Retrospective Studies ; Urologic Surgical Procedures, Male/methods* ; Child, Preschool ; Child ; Postoperative Complications/etiology* ; Urethra/surgery* ; Plastic Surgery Procedures/methods* ; Surgical Flaps ; Penis/surgery* ; Treatment Outcome ; Infant

OBJECTIVE: To explore the effect of acupuncture therapy on dysphagia in patients with Parkinson's disease. METHODS: This randomized controlled study lasted 42 days and included 112 patients with Parkinson's disease and dysphagia. Participants were randomly assigned to the experimental and control groups (56 cases each group) using the completely randomized design, all under routine treatment. The experimental group was given acupuncture therapy. The primary outcome was Penetration-Aspiration Scale (PAS). The secondary outcomes were (1) Standardized Swallowing Assessment (SSA), and (2) nutritional status including body mass index (BMI), serum albumin, prealbumin, and hemoglobin. Adverse events were recorded as safety indicators. RESULTS: One participant quitted the study midway. There were no significant differences in baseline assessment (P>0.05). After treatment, both groups showed significant improvement in PAS, SSA and nutritional status except for BMI of the control group. There were significant differences between the two groups in the PAS for both paste and liquid, SSA (25.18±8.25 vs. 20.84±6.92), BMI (19.97±3.34 kg/m²vs. 21.26 ±2.38 kg/m²), serum albumin (35.16 ±5.29 g/L vs. 37.24 ±3.98 g/L), prealbumin (248.33 ±27.72 mg/L vs. 261.39 ±22.10 mg/L), hemoglobin (119.09±12.53 g/L vs. 126.67±13.97 g/L) (P<0.05). There were no severe adverse events during the study. CONCLUSION: The combination of routine treatment and acupuncture therapy can better improve dysphagia and nutritional status in patients with Parkinson's disease, than routine treatment solely. (registration No. CLINICALTRIAL gov NCT06199323).
Humans ; Parkinson Disease/therapy* ; Deglutition Disorders/physiopathology* ; Acupuncture Therapy/adverse effects* ; Male ; Female ; Aged ; Middle Aged ; Treatment Outcome ; Nutritional Status ; Body Mass Index

Objective To understand the distribution and antimicrobial resistance profiles of bacterial strains isolated from blood cultures at Yunyang County People's Hospital from 2019 to 2023.Methods The data of bacterial isolates from blood samples and the results of antimicrobial susceptibility testing were analyzed retrospectively from 2019 to 2023 at Yunyang County People's Hospital.Results A total of 3 789 bacterial strains were isolated from blood culture,including 1 931(51.0％)strains of Gram negative bacteria and 1 858(49.0％)strains of Gram positive bacteria.Coagulase negative Staphylococcus(33.3％),Escherichia coli(25.4％),Klebsiella pneumoniae(13.7％),Staphylococcus aureus(9.9％),and Enterobacter cloacae(1.8％)were the top five bacterial pathogens.Antimicrobial susceptibility testing showed that the prevalence of methicillin-resistant strains was 27.1％in S.aureus,34.5％in S.epidermidis,and 49.9％in other coagulase-negative Staphylococcus.Methicillin resistant strains(MRSA,MRSE,and other MRCNS)showed significantly higher resistance rates to most antibiotics than corresponding methicillin-susceptible strains(MSSA,MSSE,and other MSCNS).No staphylococcal isolates were resistant to vancomycin,teicoplanin,linezolid,or tigecycline.Enterococcus faecium showed significantly higher resistance rate to antibiotics than Enterococcus faecalis.No enterococcal strains were resistant to vancomycin,teicoplanin,linezolid,or tigecycline.No streptococcal isolates were found resistant to vancomycin or linezolid.Serratia marcescens strains had a resistance rate of 25.0％to carbapenems.All other Enterobacterales species showed a resistance rate of less than 10.0％to carbapenems.No Enterobacterales isolates were found resistant to tigecycline.The resistance rates of P.aeruginosa to imipenem and meropenem were 5.7％and 3.8％,respectively.No P.aeruginosa isolates were found resistant to colistin.The resistance rates of Acinetobacter baumannii to imipenem and meropenem were 41.4％and 38.0％,respectively.Conclusions The proportion of Gram negative bacteria is slightly higher than that of Gram positive bacteria in the bacterial isolates from blood samples at Yunyang County People's Hospital.The prevalence of MRSA and MRCNS is relatively high,while A.baumannii and S.marcescens showed high resistance rates to carbapenems.Antimicrobial resistance surveillance should be strengthened for the bacterial isolates from blood samples in order to learn the changing resistance profiles,use antibiotics reasonably,and prevent the spread of drug-resistant bacteria.

Objective: To explore the association of health literacy with overweight and obesity among middle school students in Chongqing, so as to provide evidence for obesity prevention and control strategies. Methods: From November to December 2019, a stratified cluster sampling method was used to select 7 851 middle school students from 8 complete middle schools across 4 districts/counties in Chongqing. Participants completed the Adolescent Health Literacy Questionnaire and underwent nutritional status assessments. Chisquare tests and multivariate Logistic regression analyses were performed to evaluate associations. Results: The prevalence of overweight and obesity among adolescents was 12.95%. The overall health literacy rate and rates for functional, interactive, and critical health literacy dimensions were 62.01%, 66.02%, 50.07%, and 72.42%, respectively. Significant differences in overweight and obesity prevalence were observed across districts/counties, urban/rural areas, sex, school stages, and onlychild status (χ2=25.93, 3.86, 80.55, 8.80, 6.43, P<0.05). After adjusting for confounding factors, multivariate Logistic regression revealed that middle school students with overall health literacy (OR=0.86, 95%CI=0.75-0.99), interactive health literacy (OR=0.85, 95%CI=0.74-0.97), and critical health literacy (OR=0.84, 95%CI=0.73-0.98) had a lower risk of overweight and obesity (P<0.05). Conclusions Health literacy is inversely associated with overweight and obesity among middle school students. Strengthening health education and improving interactive and critical health literacy may create favorable conditions for adolescent overweight and obesity prevention and control.

Objective:To explore the time variations of the influence of the ultra-high dose rate irradiation (FLASH irradiation, FLASH-IR) and conventional dose rate irradiation (CONV-IR) of electron beams under different doses on the energy metabolism of triple-negative breast cancer cells MDA-MB-231.Methods:The basal metabolism of the MDA-MB-231 cells and normal breast epithelial cells MCF-10A was compared using a Seahorse XF Pro Metabolic Analyzer. Based on an irradiation platform with a thermionic cathode electron accelerator (6 MeV), the MDA-MB-231 cells were exposed to FLASH-IR (106 Gy/s) and CONV-IR (0.1 Gy/s) at 2 and 14 Gy, respectively. Meanwhile, a sham irradiation group was established under identical culture conditions. The mitochondrial metabolism and glycolytic metabolism of the cells at 4, 24, and 48 h post-irradiation were analyzed.Results:Compared to the MCF-10A cells, the MDA-MB-231 cells exhibited a greater reliance on glycolytic metabolism. Compared to those of the sham irradiation group, MDA-MB-231 cells in the 2 Gy CONV-IR group showed up-regulated ATP-linked respiration at 4, 24, and 48 h post-irradiation ( t = 2.69-3.70, P < 0.05). Their glycolytic level and glycolytic capacity were up-regulated only at 4 h post-irradiation and were down-regulated at 48 h ( t = 2.79, -4.44, P < 0.05). In contrast, there was no statistically significant difference in these indicators between the FLASH-IR and CONV-IR groups ( P > 0.05). However, the proton leak of the MDA-MB-231 cells in the FLASH-IR group was relatively down-regulated at 4 h post-irradiation and was significantly up-regulated at 24 h and 48 h post-irradiation compared with the CONV-IR group ( t = -2.45, 3.19, 6.51, P < 0.05). At 14 Gy, the MDA-MB-231 cells in the CONV-IR group showed progressively increased mitochondrial and glycolytic metabolism across all time points ( t = 2.48-12.14, P < 0.05). Notably, compared with the CONV-IR group, the MDA-MB-231 cells in the FLASH-IR group exhibited more significantly up-regulated basal respiration, ATP-linked respiration, and non-mitochondrial oxygen consumption ( t = 2.56-6.51, P < 0.05), as well as a higher glycolytic capacity at 24 h post-irradiation ( t = 2.86, P < 0.05). Conclusions:Low-dose (2 Gy) FLASH-IR induces relatively up-regulated proton leak in breast cancer cells MDA-MB-231 at 24 h post-irradiation. In contrast, under high-dose (14 Gy) FLASH-IR, the MDA-MB-231 cells show more pronounced mitochondrial metabolic stress and a higher demand for energy metabolism.

Objective To understand the distribution and antimicrobial resistance profiles of bacterial strains isolated from blood cultures at Yunyang County People's Hospital from 2019 to 2023.Methods The data of bacterial isolates from blood samples and the results of antimicrobial susceptibility testing were analyzed retrospectively from 2019 to 2023 at Yunyang County People's Hospital.Results A total of 3 789 bacterial strains were isolated from blood culture,including 1 931(51.0％)strains of Gram negative bacteria and 1 858(49.0％)strains of Gram positive bacteria.Coagulase negative Staphylococcus(33.3％),Escherichia coli(25.4％),Klebsiella pneumoniae(13.7％),Staphylococcus aureus(9.9％),and Enterobacter cloacae(1.8％)were the top five bacterial pathogens.Antimicrobial susceptibility testing showed that the prevalence of methicillin-resistant strains was 27.1％in S.aureus,34.5％in S.epidermidis,and 49.9％in other coagulase-negative Staphylococcus.Methicillin resistant strains(MRSA,MRSE,and other MRCNS)showed significantly higher resistance rates to most antibiotics than corresponding methicillin-susceptible strains(MSSA,MSSE,and other MSCNS).No staphylococcal isolates were resistant to vancomycin,teicoplanin,linezolid,or tigecycline.Enterococcus faecium showed significantly higher resistance rate to antibiotics than Enterococcus faecalis.No enterococcal strains were resistant to vancomycin,teicoplanin,linezolid,or tigecycline.No streptococcal isolates were found resistant to vancomycin or linezolid.Serratia marcescens strains had a resistance rate of 25.0％to carbapenems.All other Enterobacterales species showed a resistance rate of less than 10.0％to carbapenems.No Enterobacterales isolates were found resistant to tigecycline.The resistance rates of P.aeruginosa to imipenem and meropenem were 5.7％and 3.8％,respectively.No P.aeruginosa isolates were found resistant to colistin.The resistance rates of Acinetobacter baumannii to imipenem and meropenem were 41.4％and 38.0％,respectively.Conclusions The proportion of Gram negative bacteria is slightly higher than that of Gram positive bacteria in the bacterial isolates from blood samples at Yunyang County People's Hospital.The prevalence of MRSA and MRCNS is relatively high,while A.baumannii and S.marcescens showed high resistance rates to carbapenems.Antimicrobial resistance surveillance should be strengthened for the bacterial isolates from blood samples in order to learn the changing resistance profiles,use antibiotics reasonably,and prevent the spread of drug-resistant bacteria.

Objective:To explore the time variations of the influence of the ultra-high dose rate irradiation (FLASH irradiation, FLASH-IR) and conventional dose rate irradiation (CONV-IR) of electron beams under different doses on the energy metabolism of triple-negative breast cancer cells MDA-MB-231.Methods:The basal metabolism of the MDA-MB-231 cells and normal breast epithelial cells MCF-10A was compared using a Seahorse XF Pro Metabolic Analyzer. Based on an irradiation platform with a thermionic cathode electron accelerator (6 MeV), the MDA-MB-231 cells were exposed to FLASH-IR (106 Gy/s) and CONV-IR (0.1 Gy/s) at 2 and 14 Gy, respectively. Meanwhile, a sham irradiation group was established under identical culture conditions. The mitochondrial metabolism and glycolytic metabolism of the cells at 4, 24, and 48 h post-irradiation were analyzed.Results:Compared to the MCF-10A cells, the MDA-MB-231 cells exhibited a greater reliance on glycolytic metabolism. Compared to those of the sham irradiation group, MDA-MB-231 cells in the 2 Gy CONV-IR group showed up-regulated ATP-linked respiration at 4, 24, and 48 h post-irradiation ( t = 2.69-3.70, P < 0.05). Their glycolytic level and glycolytic capacity were up-regulated only at 4 h post-irradiation and were down-regulated at 48 h ( t = 2.79, -4.44, P < 0.05). In contrast, there was no statistically significant difference in these indicators between the FLASH-IR and CONV-IR groups ( P > 0.05). However, the proton leak of the MDA-MB-231 cells in the FLASH-IR group was relatively down-regulated at 4 h post-irradiation and was significantly up-regulated at 24 h and 48 h post-irradiation compared with the CONV-IR group ( t = -2.45, 3.19, 6.51, P < 0.05). At 14 Gy, the MDA-MB-231 cells in the CONV-IR group showed progressively increased mitochondrial and glycolytic metabolism across all time points ( t = 2.48-12.14, P < 0.05). Notably, compared with the CONV-IR group, the MDA-MB-231 cells in the FLASH-IR group exhibited more significantly up-regulated basal respiration, ATP-linked respiration, and non-mitochondrial oxygen consumption ( t = 2.56-6.51, P < 0.05), as well as a higher glycolytic capacity at 24 h post-irradiation ( t = 2.86, P < 0.05). Conclusions:Low-dose (2 Gy) FLASH-IR induces relatively up-regulated proton leak in breast cancer cells MDA-MB-231 at 24 h post-irradiation. In contrast, under high-dose (14 Gy) FLASH-IR, the MDA-MB-231 cells show more pronounced mitochondrial metabolic stress and a higher demand for energy metabolism.

Aim To investigate the mechanism of curcumin inhibition of oxidative stress on osteogenic differentiation and its dose-dependent anti-osteoporosis effect. Methods Cellular oxidative stress models were used, different concentrations of curcumin were added to determinethebone formation markers, and the potential signaling pathways involvedwere detected. Meanwhile, the mouse model of osteoporosis ( ovariecto- mized, 0VX) was used to confirm its effect against osteoporosis. Results In vitro experiments found that low concentrations of curcumin (1-10 μmol · L

OBJECTIVE To study the toxicokinetics and tissue distribution characteristics of alpha-amanitin in rats.METHODS The tail venous blood was collected from SD rats before and 5,10,20,30 and 45 min,1,1.5,2.5,4 and 8 h after intraperitoneal injection of alpha-amanitin(1.5 mg·kg-1),and the concentration of alpha-amanitin in blood was determined by liquid chromatography-mass spectrometry(LC-MS/MS).DAS 2.0 software was used to analyze and plot the drug-time curve with toxicokinetic parame-ters.Based on the toxicokinetics results,18 SD rats were randomly divided into three groups.The rats were sacrificed,and left ventricular arterial(LVA)blood and 9 types of tissue samples involving the heart,liver,spleen,lung,kidney,whole brain,small intestine,stomach wall and testis were collected 15 min,40 min and 2.5 h after dosing,and the concentrations of alpha-amanitin were measured by LC-MS/MS to obtain the tissue distribution results of alpha-amanitin in SD rats.RESULTS Toxicokinetics studies revealed that the peak blood concentration(Cmax)was(633±121)μg·L-1,the elimination half-life(T1/2)was(0.72±0.37)h,and the peak time(Tmax)was(0.52±0.16)h.The total clearance rate(CLz)was(1.62±0.26)L·h·kg-1,the area under the curve(AUC0-t)was(946±183)μg·h·L-1,and the mean reten-tion time(MRT0-t)was(1.18±0.17)h.The apparent volume of distribution(Vz)was(1.65±0.86)L·kg-1.The results of tissue distribution study showed that alpha-amanitin was widely distributed in SD rats with the highest concentration in the kidney,followed by the lung,small intestines,stomach wall,LVA blood and liver,but was low in the heart,spleen,testicles and other tissues,and very low in the brain.Alpha-amanitin was absorbed and eliminated quickly,peaked at 40 min in each tissue,and the concen-tration was minimized after 2.5 h.CONCLUSION The absorption and elimination of alpha-amanitin by intraperitoneal injection are rapid in SD rats,and the blood concentration reaches the peak about 31 min after administration,but can not be detected 4 h later.Alpha-amanitin is mainly distributed in the kidney,followed by the tissues and metabolic organs with rich blood flow,such as the lung,small intestines,stomach wall,LVA blood and liver.The content of alpha-amanitin is low in the heart,spleen,testicles and other tissues,and very low in the brain.It is speculated that it may have toxic targeting effect on the kidney and low blood-brain barrier permeability.