BACKGROUND:Studies have reported that alendronate intake significantly increases bone mineral density in patients with osteoporosis. OBJECTIVE:To analyze and compare the changes in metabolites before and after alendronate intervention in ovariectomized rats by chromatography-mass spectrometry,and to further explore the specific mechanism and target of alendronate in the treatment of osteoporosis. METHODS:A total of 36 female Sprague-Dawley rats were randomly divided into model group,alendronate sodium group and sham operation group.The osteoporosis model was established by ovariectomy in the first two groups.Four weeks after modeling,the rats in the alendronate group were intragastrically given alendronate sodium,while those in the sham operation group and model group were given equal volume of normal saline.After 12 weeks of continuous gavage,the metabolites of the lumbar spine were analyzed by chromatography-mass spectrometry,and the common differential metabolites were obtained,which were analyzed by bioinformatics such as Kyoto Gene and Genome Encyclopedia pathway. RESULTS AND CONCLUSION:Totally 17 different metabolites were obtained in the three groups.The enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes showed that alendronate sodium could regulate unsaturated fatty acid biosynthesis,linoleic acid metabolism and other pathways to protect ovariectomized rats.These results indicate that alendronate sodium may exert its anti-osteoporosis effect by interfering with unsaturated fatty acid bioanabolism and linoleic acid metabolism,so as to achieve the purpose of preventing osteoporosis

Objective:To evaluate the clinical value of cognitive and motor function in predicting conversion to neurodegenerative disorders in patients with isolated rapid eye movement sleep behavior disorder (iRBD).Methods:Forty-seven patients with iRBD were collected from the Department of Neurology of Tianjin Medical University General Hospital and Tianjin Medical University General Hospital Airport Site during October 2018 and June 2022. All participants received comprehensive evaluations of cognitive and motor function at baseline. The visuospatial function was evaluated by Rey-Osterrieth Complex Figure Test (ROCF)-copy, the memory function was evaluated by Auditory Verbal Learning Test and ROCF-recall, the attention-executive function was evaluated by Trail Making Test (TMT) and Stroop Color-Word Test, and the language function was evaluated by Boston Naming Test. The motor function was evaluated by Unified Parkinson′s Disease Rating Scale-Ⅲ, Alternate-tap Test (ATT), and 3-meter Timed Up and Go Test. The iRBD patients with phenoconversion were identified during follow-up. Receiver operating characteristic curve and generalized linear model Logistic regression were applied to identify the optimal combination of cognitive and motor tests in distinguishing the converters from non-converters in patients with iRBD. Multivariate Cox regression analyses were applied to evaluate the independent risk factors in predicting conversion to neurodegenerative diseases in patients with iRBD.Results:The median follow-up duration was 3 years. Forty-five iRBD patients were included in the analysis eventually, as 2 dropped out at follow-up. Twenty-one iRBD patients developed neurodegenerative disorders, with 14 presenting motor phenotype and 7 cognitive phenotype. Baseline ROCF-copy, TMT-A and ATT were best combination in identifying iRBD patients with phenoconversion [sensitivity: 90.0%, specificity: 87.5%, area under curve (AUC): 0.931, P<0.001]. Baseline TMT-A and ATT were best combination in identifying iRBD patients with motor phenotype conversion (sensitivity: 100.0%, specificity: 66.7%, AUC: 0.872, P<0.001); Baseline TMT-A performed best in identifying iRBD patients with cognitive phenotype conversion (sensitivity: 83.3%, specificity: 91.7%, AUC: 0.917, P<0.001). Multivariate Cox regression analysis showed that individuals with poorer performance of TMT-A (cut-off value: 63.0 s) and ATT (cut-off value: 205.5 taps/min) than the cut-off values at baseline had higher risks for developing to neurodegenerative disorders, with HR values of 5.455 (95% CI 1.243-23.941, P=0.025) and 11.279 (95% CI 1.485-85.646, P=0.019), respectively. Conclusions:In iRBD, ROCF-copy, TMT-A and ATT served as optimum combination in predicting phenoconversion, whereas TMT-A and ATT served as optimum combination in predicting motor phenotype, and TMT-A performed best in predicting cognitive phenotype. The performance in TMT-A and ATT in iRBD could predict the risk of developing to neurodegenerative disorders independently.

Objective:This study aims to demonstrate the feasibility of using Bio-layer Interferometry (BLI) for label-free detection of peripheral blood biomarkers, using C-reactive protein (CRP) as a model molecule.Methods:A total of 85 clinical remnant serum samples from routine laboratory tests were collected from Fuwai Hospital, Chinese Academy of Medical Sciences, from July 2021 to May 2022. The biotinylated anti-CRP antibody was immobilized onto streptavidin-functionalized BLI probes. The GatorPrime BLI system was used to detect series of diluted CRP standards in real-time, and to generate dynamic binding curves for establishing standard curves based on the relationship between concentration and initial binding rates. The sensitivity of the method, including the limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ), was evaluated according to Clinical & Laboratory Standards Institute (CLSI) guidelines. Serum samples and third-party quality control materials were used to evaluate the precision, while linearity was verified through the dilution of a high-concentration serum series. Method comparison between the label-free BLI assay and conventional clinical laboratory immunoassays was conducted using Passing-Bablok regression and Spearman correlation analysis.Results:The GatorPrime BLI system demonstrated a dynamic detection range of 0.6-300 mg/L for CRP standards, and the linearity within this range was validated using serum samples. The LoB, LoD, and LoQ for this method were determined to be 0.246 mg/L, 0.573 mg/L, and 2.158 mg/L, respectively. Precision analysis showed that the total laboratory imprecision of the four levels of quality control materials (21.15-57.26 mg/L) ranged from 5.8% to 9.0%, and the total imprecision of the two serum samples (2.32 mg/L and 100.06 mg/L) was 22.3% and 7.4%, respectively. Methodological comparison with two commonly used clinical laboratory immunoassays revealed a strong correlation with our method(Passing-Bablok regression: Y=?1.065+1.119 X and Y=?0.452+1.034 X, r=0.993 and r=0.976, P<0.001). Conclusions:The label-free BLI immunoassay method enables the detection of CRP across a broad concentration range in blood samples, with analytical performance meeting the requirements for laboratory testing. This method shows potential as a reliable and efficient alternative for CRP measurement in clinical practice.

Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets between complex diseases and CHM formulas,we developed an artificial intelligence-based quantitative predictive algorithm(DeepTCM).DeepTCM has gone through multilevel model cali-bration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling,molecular and theoretical levels of traditional Chinese medicine(TCM).As an example,our model simulated the optimal CHM formulas for the treatment of coronary heart disease(CHD)with depression,and through model sensitivity analysis,we calculated the balanced scoring of the formulas.Furthermore,we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions.Finally,we experimentally confirmed the thera-peutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice.This novel multiscale model opened up a new avenue to combine"disease syndrome"and"macro micro"system modeling to facilitate translational research in CHM formulas.

Objective To analyze the emergency treatment protocols and nursing measures for patients with diquat and paraquat poisoning,aiming to provide references for updating future clinical practice.Methods A retrospective study was conducted involving 53 patients with diquat and paraquat poisoning admitted to the department of emergency of the First Affiliated Hospital of Wenzhou Medical University from January 1,2019,to December 31,2023.The patients were divided into survival and death groups based on their prognosis.Clinical data were collected to compare organ dysfunction,the proportion of hemoperfusion(HP),average number of HP sessions,the proportion of blood purification,average duration of blood purification,and the proportion of HP combined with continuous renal replacement therapy(CRRT)between two groups of patients with different prognoses.Results Among the 53 patients,27(50.94%)were male and 26(49.06%)were female;with an age range of 14 to 86 years and a mean age of(38.13±19.68)years.Fifty-two cases were due to intentional ingestion,and 1 was accidental.The detected blood concentrations of diquat ranged from 57.38 to 119762.00 μg/L,while those of paraquat ranged from 60.12 to 71 244.89 μg/L.Forty patients developed multiple organ dysfunction syndrome(MODS),with 38 ultimately progressing to multiple organ failure,primarily affecting the gastrointestinal tract,kidneys,and liver.After aggressive treatment and nursing,the blood concentrations of 13 patients(24.53%)dropped below 50 μg/L,and they were discharged after 4 to 34 days of hospitalization.Thirty-two patients'families opted for withdrawal of treatment and discharge,with subsequent confirmation of death after follow-up,hospital stay:1-4 days.Eight patients died in-hospital,hospital stay:1-3 days,resulting in a total mortality rate of 40 cases(75.47%).Compared to the survival group,the death group had significantly higher rate of neurological,renal,respiratory,and liver injuries[neurological:90.00%(36/40)vs.15.38%(2/13),renal:95.00%(38/40)vs.69.23%(9/13),respiratory:97.50%(39/40)vs.30.77%(4/13),liver injury:85.00%(34/40)vs.46.15%(6/13),all P<0.05].Furthermore,the death group had significantly lower average number of HP sessions and average duration of blood purification compared to the survival group[average number of HP sessions:4.35±2.42 vs.6.62±1.17,average duration of blood purification time(days):1.53±1.09 vs.5.23±3.90,both P<0.05].Conclusions Poisoning with a mixture of diquat and paraquat is life-threatening and associated with a high mortality.In addition to systematic treatment,individualized and dynamic nursing support should be provided,including close monitoring of the manifestations and laboratory indicators of affected organ systems.Therefore,optimization treatment protocols during the peak mortality period may help reduce mortality in patients with diquat and paraquat poisoning.

Objective:To investigate the impact of BMI1 expression in OSCC on the recruitment and differentiation of tumor-associat-ed macrophages(TAMs).Methods:BMI1 expression in 519 cases of OSCC tissues and 44 normal controls was analyzed using online datasets of GEPIA 2.0,and validated in 3 cases of OSCC samples and controls by qRT-PCR and western blotting.The function of BMI1/NF-κB axis during OSCC carcinogenesis was investigated by CCK8 assays,wound healing test and transwell assays.Macrophage phenotypes and recruitment were determined using qRT-PCR and western blotting following coculture of the cells with human monocyte cells(THP-1)by OSCC conditioned medium.Moreover,a cell line-derived xenograft(CDX)model was used to detect the effect of BMI1 on tumor growth in vivo.Results:Compared with the normal tissues and cells,the expression level of BMI1 in OSCC tissues and cells was significantly upregulated.BMI1 knockdown impaired the proliferation,migration,and invasion abilities of OSCC cell lines in NF-κB-dependent manner.Furthermore,OSCC cells with high BMI1 expression inhibited the migration of THP-1 cells,promoted M2-like macrophage polarization through NF-κB pathway in vitro.Xenograft experiments further confirmed the inhibitory effect of BMI1 knockdown on the tumorigenesis ability of OSCC cells in vivo.Conclusion:BMI1 promotes M2-like polarization by regulating NF-κB and may be used as a potential therapeutic target for antitumor immunity.

Circadian rhythm disruption is a universal phenomenon that is associated with a combination of internal and external factors, with internal factors referring to disturbances in the intrinsic regulatory mechanisms of sleep-wake behavior, and external factors including changes in sleep habits, severe sleep deprivation, shift work, social jet lag, prolonged exposure to nighttime light, and late nighttime eating. Shift work, as a common occupational factor, can lead to disruption of the central/ peripheral biological clock which regulates the expression of almost the entire genome, and the disruption of the biological clock can lead to genetic variants, hormonal secretion abnormalities, insulin resistance, oxidative stress, and systemic inflammation, which are risk factors for obesity. In the context of rapid advancement of global economy and industrialization, the prevalence of simple obesity in the traditional cognitive category is increasing in a linear trend, while the incidence of abdominal obesity, which is closely related to metabolic disorders, is also showing an increasing trend. In recent years, the mechanism of circadian rhythm disorder and obesity associated with shift work has attracted much attention, and this article summarized the latest research progress, aiming to provide a basis for the prevention and treatment of obesity caused by circadian rhythm disruption due to shift work.

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC₈₀ ≥ 64 μg/mL) could be efficiently recovered (MIC₈₀ = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

Objective:To investigate the association between split foot and electrophysiology in patients with amyotrophic lateral sclerosis (ALS).Methods:The clinically definite or clinically probable ALS patients hospitalized in the Department of Neurology, the First Medical Center of Chinese People′s Liberation Army General Hospital from April 2021 to December 2022 were prospectively collected. From April 2021 to December 2022, patients who visited the Chinese People′s Liberation Army General Hospital for other reasons without abnormal electrophysiological examination were collected as the control group. The incidence of split leg [the limb whose modified Medical Research Council Muscle Strength Scale (mMRC) score of ankle dorsiflexors was lower than that of ankle plantarflexors] in ALS patients was calculated, and the incidence of split foot (the limb whose mMRC score of hallux dorsiflexors was lower than that of hallux plantarflexors) in ALS patients was calculated. The amplitude of compound muscle action potential (CMAP) of common peroneal nerve and tibial nerve was detected to observe the involvement of motor neurons innervating ankle dorsiflexors and ankle plantarflexors. The characteristics of split leg and split foot in ALS patients were analyzed from the perspective of muscle strength, and the characteristics of split foot in ALS patients were analyzed from the perspective of electrophysiology. Receiver operating characteristic (ROC) curve was used to analyze the sensitivity and specificity of peroneal nerve/tibial nerve CMAP amplitude ratio in distinguishing ALS patients from controls.Results:A total of 101 ALS patients with lower limb involvement and 110 controls with normal lower limb muscle strength were collected. Among the 101 ALS patients with lower limb involvement, strength of ankle plantarflexors was greater than that of ankle dorsiflexors in 35.64% (36/101) patients, strength of ankle dorsiflexors was greater than that of ankle plantarflexors in 5.94% (6/101) patients, and strength of ankle plantarflexors and ankle dorsiflexors was equal in 58.42% (59/101) patients. Strength of hallux dorsiflexors was lower than that of hallux plantarflexors in 53.47% (54/101) patients, strength of hallux dorsiflexors was greater than that of hallux plantarflexors in 1.98% (2/101) patients, and the strength of hallux dorsiflexors and hallux plantarflexors was equal in 44.55% (45/101) patients. The incidence of split leg was negatively correlated with age ( OR=0.25, 95% CI 0.16-0.40, P<0.05), course of disease ( OR=0.52, 95% CI 0.38-0.80 P<0.05) and ALS functional revised scores ( OR=0.29, 95% CI 0.12-0.67, P<0.05). The incidence of split foot was negatively correlated with the onset time of lower limb symptoms ( OR=0.96, 95% CI 0.93-0.99, P<0.05). Compared with the control group, the differences of the decrease of CMAP amplitude in the common peroneal nerve and tibial nerve [the common peroneal nerve (6.45±2.56) mV vs (3.63±1.83) mV, tibial nerve (12.87±4.72) mV vs (9.18±6.22) mV] were statistically significant ( t=-4.65, t=-3.44, both P<0.001) and the differences of the peroneal nerve/tibial nerve CMAP amplitude ratio (0.54±0.24 vs 0.36±0.18) decrease was statistically significant ( t=-4.31, P<0.001) in patients with split foot. ROC curve analysis showed that the area under the ROC curve of CMAP amplitude ratio of common peroneal nerve/tibial nerve in ALS patients with split foot was 0.70, indicating that the accuracy of CMAP amplitude of common peroneal nerve/tibial nerve in distinguishing ALS patients from controls was low. Conclusions:In ALS patients with lower limb involvement, strength of ankle dorsiflexors is weaker than that of ankle plantarflexors, and strength of hallux dorsiflexors is weaker than that of hallux plantarflexors. At the diagnostic level, the CMAP amplitude ratio of common peroneal nerve/tibial nerve in ALS patients with split foot has a lower accuracy in the diagnosis of ALS.

Human papillomavirus (HPV) is one of the most common sexually transmitted pathogens. It can cause a variety of diseases such as condyloma acuminatum, anal cancer, penile cancer and oropharyngeal cancer in men, resulting in a high disease burden. With the development of society, the application of HPV vaccines in males has attracted more attention. Currently, there are many clinical trials and real-world research results of HPV vaccines applied to boys and men worldwide, and many countries have introduced HPV vaccination for underage boys into their national immunization programs. This article intended to review the research progress in the efficacy of HPV vaccines in male population.