Computational approaches, encompassing both physics-based and machine learning (ML) methodologies, have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities. The human dopamine (DA) transporter (hDAT) is the primary therapeutic target of numerous psychiatric medications. However, traditional hDAT-targeting drugs, which interact with the primary binding site, encounter significant limitations, including addictive potential and stimulant effects. In this study, we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape (WHALES) descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs. Initially, WHALES descriptors facilitated a similarity search, employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates. Consequently, from a compound library of 4,921 marketed and clinically tested drugs, we identified 27 candidate atypical inhibitors. Subsequently, ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates, while induced-fit docking (IFD) was performed to estimate their binding affinities. Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities. Among these, three exhibited significant inhibitory potency, with half maximal inhibitory concentration (IC₅₀) values of 0.753 μM, 0.542 μM, and 1.210 μM, respectively. Finally, molecular dynamics (MD) simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation. In conclusion, our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Objective To assess the therapeutic efficacy of low-intensity focused ultrasound(LIFU)on knee arthrofibrosis in rats and explore its underlying mechanisms.Methods Fifteen male SD rats(8 weeks old,weighing 250～300 g)were randomly divided into a blank control group,a model group,and an ultrasound treatment group,with 5 animals in each group.Rat model of knee joint stiffness was established in the model and ultrasound treatment group.The rats in the ultrasound group received LIFU intervention(frequency:1 MHz,power:1.5 W,20 min per session,5 times/week)for 4 weeks.The knee ranges of motion(ROM,flexion and extension)were measured in all 3 groups at 0,14 and 28 d after intervention.Histological analysis was conducted for the morphological changes in the posterior capsular area of the knee.After the synovial fibroblasts were primary isolated from rat knee joints,the cells were divided into blank control,LIFU,TGF-β(10 ng/mL),and TGF-β+LIFU groups.Changes in fibrosis-related indicators and the TGF-β/Smad signaling pathway were assessed in each group.Results In the animal experiments,LIFU intervention for 14 d resulted in significantly improved flexion-extension ROM in knee joints when compared with the rats in the model group(P<0.05),and the improvement was more obvious at 28 d after intervention(P<0.05).After 28 d of LIFU intervention,the fibrosis of the posterior capsule of the knee joint was notably improved in the ultrasound group than the model group,and the expression levels of fibrosis-related indicators(α-SMA,TGF-β)were decreased(P<0.05).In the cellular experiments,the TGF-β group exhibited remarkable up-regulation of fibrosis-related molecules(α-SMA,COL1A1,COL3A1)at both protein and mRNA levels(P<0.05),and activation of the TGF-β/Smad signaling pathway when compared to the blank control group.While LIFU intervention inhibited the expression of TGF-β-induced upregulation of fibrotic indicators(α-SMA,COL1A1,COL3A1)and the activation of TGF-β/Smad signaling pathway(P<0.05).Conclusion LIFU can effectively improve knee arthrofibrosis in rats,which potentially through the inhibition of fibroblast activation and modulation of the TGF-β/Smad signaling pathway.

Computational approaches,encompassing both physics-based and machine learning(ML)methodolo-gies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychi-atric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxi-cological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter re-uptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC50)values of 0.753 μM,0.542 μM,and 1.210 μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were con-ducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Bone tissue engineering(BTE)is expected to be used as an autologous bone graft substitute for bone defects,and in the se-lection of BTE scaffold materials,collagen(Col)and hydroxyapatite(HA)have attracted attention due to their unique biomimetic ad-vantages.Collagen/hydroxyapatite(CHA)composite scaffolds made by combining the two have been shown to have excellent biocompat-ibility and bone-enhancing potential in various in vitro,in vivo,and clinical studies.With the development of three-dimensional(3D)printing technology in the field of tissue engineering,bone scaffolds constructed using 3D printing methods have been shown to possess superior clinical potential.This review describes new advances in 3D printed CHA composite scaffolds and introduces the application of 3D printed CHA scaffolds in oral and maxillofacial bone regenerative repair.

Cognitive impairment is one of the manifestations of nervous system injury,which is mainly closely related to neurodegeneration,and the incidence rate is increasing year by year,which has seriously affected the health level of the population.The gut microbiota plays an important role in the health of the body and participates in the regulation of the cognitive behavior of body.The microbiome-gut-brain axis acts as a bridge connecting gut microbiota and the nervous system,and plays a regulatory role between gut microbiota and the nervous system.Therefore,this review summarizes the latest progress in the effects of gut microbiota and nervous system on the cognitive ability of body through the bidirectional regulation of neurotransmitters,gut microbiota derivatives,neuroinflammation,oxidative stress,autophagy and their crosstalk through the microbial-intestinal-brain axis,and providing a reference for the clinical research of targeted transplantation of gut microbiota for preventing and treating cognitive disorders.

Cognitive impairment is one of the manifestations of nervous system injury,which is mainly closely related to neurodegeneration,and the incidence rate is increasing year by year,which has seriously affected the health level of the population.The gut microbiota plays an important role in the health of the body and participates in the regulation of the cognitive behavior of body.The microbiome-gut-brain axis acts as a bridge connecting gut microbiota and the nervous system,and plays a regulatory role between gut microbiota and the nervous system.Therefore,this review summarizes the latest progress in the effects of gut microbiota and nervous system on the cognitive ability of body through the bidirectional regulation of neurotransmitters,gut microbiota derivatives,neuroinflammation,oxidative stress,autophagy and their crosstalk through the microbial-intestinal-brain axis,and providing a reference for the clinical research of targeted transplantation of gut microbiota for preventing and treating cognitive disorders.

Bone tissue engineering(BTE)is expected to be used as an autologous bone graft substitute for bone defects,and in the se-lection of BTE scaffold materials,collagen(Col)and hydroxyapatite(HA)have attracted attention due to their unique biomimetic ad-vantages.Collagen/hydroxyapatite(CHA)composite scaffolds made by combining the two have been shown to have excellent biocompat-ibility and bone-enhancing potential in various in vitro,in vivo,and clinical studies.With the development of three-dimensional(3D)printing technology in the field of tissue engineering,bone scaffolds constructed using 3D printing methods have been shown to possess superior clinical potential.This review describes new advances in 3D printed CHA composite scaffolds and introduces the application of 3D printed CHA scaffolds in oral and maxillofacial bone regenerative repair.

Objective To introduces drug treatment and individualized pharmaceutical care for a patient with dilated cardiomyopathy digoxin poisoning and provides ideas for pharmaceutical care.Methods The pharmacist used therapeutic drug management to analyze the course of drug treatment before and after hospitalization,combined with therapeutic drug monitoring and drug-gene detection,to analyze the causes of poisoning in digoxin from the perspectives of underlying diseases,polymor-phism,drug dosage,combination of drugs,physiological and other pathological factors,and to assist in clinical drug reformula-tion and optimization of drug treatment regimens.Results The clinician accepted the clinical pharmacist's suggestion.The pa-tient had a good prognosis,and digoxin poisoning did not occur in the later period.Conclusion This case provides a feasible treatment for dilated cardiomyopathy and other patients with digoxin intoxication;it can be used as a reference for the prevention and treatment of digoxin poisoning and provide a new direction for the development of hospital pharmaceutical care and pharma-ceutical professionals.

Objective To analyze the effect of death under-reporting on the regional longevity-related deaths proportion and provide some evidence for its application in the regional longevity level evaluation.Methods National deaths registration data in 2019 were obtained from the National mortality surveillance system and the crude mortality of each county were calculated.According to different crude mortality criteria(≥4.5‰,≥5.0‰,≥6.0‰,≥7.0‰,respectively),a total of 9 indicators of death proportion of the national level were computed based on the corresponding number of counties included.Standard deviation and coefficient of variation were adopted to evaluate the stability of each indicator.At the provincial level and prefecture level,Bland-Altman plot was adopted to evaluated the consistence of the 9 indicators of death proportion in two different conditions,namely all the monitored counties included and only those counties with the crude mortality greater than 6.0‰ included,respectively.Results At the national level,the proportions of centenary death had the smallest standard deviation(0.01～0.02)followed by the proportions of longevity death(0.13～0.18),while the proportions of deaths aged 80 years and older had the largest standard deviation(0.20～0.33).Those indicators named as 80+/60+and 100+/90+had the smallest coefficient of variation(0.43～0.44),while 100+/all and 90+/all had the largest(1.69～1.80).At the provincial and prefecture scale,the 95%limits of agreement(LoA)of all the 9 proportions were beyond the corresponding professional acceptable variation,which means that those indicators in the two conditions cannot be replaced with each other.Conclusion Death under-reporting has little effect on the proportion of longevity-related deaths at the national level but has a great impact on provincial level or prefecture level.Counties or districts with high death data completeness(crude mortality greater than 6.0‰)can only be included to obtain the longevity-related deaths proportion at provincial or prefecture level to ensure their accuracy.

Objective:To explore the mechanism of long non-coding RNA RP11-79H23.3 in the development and progression of prostate cancer.Methods:The lnCAR database was used to analyze the RP11-79H23.3 content in prostate cancer tissues and adjacent tissues. RP11-79H23.3 content in prostate cancer cell lines C4-2B, LNCaP, DU-145, and 22Rv1 was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Taking 22Rv1 as the research target, colony formation experiments and scratch experiments were used to detect the effects of overexpression of RP11-79H23.3 on the proliferation and migration of 22Rv1 cells. The LncRNome and lncACTdb databases were used to predict the downstream gene and binding sequences of RP11-79H23.3. The Cancer Genome Atlas (TCGA) database was used to analyze the correlation between RP11-79H23.3 and miR-410 expression in prostate cancer tissues. The binding of RP11-79H23.3 and miR-410 was confirmed by dual-luciferase reporter gene experiment. The effect of RP11-79H23.3 on the expression of miR-410 was detected by RT-qPCR. Western blotting was used to detect the effect of RP11-79H23.3 on the expression of phosphatase and tensin homolog/protein kinase B/mammalian target of rapamycin (PTEN/AKT/mTOR) signaling pathway proteins in 22Rv1 cells. The measurement data were expressed as mean ± standard deviation ( ± s), paired sample t-test was used for comparison between two groups, and one-way analysis of variance was used for comparison between multiple groups. Results:Compared with adjacent tissues, RP11-79H23.3 was lowly expressed in prostate cancer tissues ( P<0.01). Compared with normal prostate epithelial cells RWPE-1, RP11-79H23.3 was lowly expressed in prostate cancer cell lines C4-2B, LNCaP, DU-145, and 22Rv1 ( P<0.05). The expression of RP11-79H23.3 in 22Rv1 cells in the control group and RP11-79H23.3 group were 1.02 ± 0.30 and 8.94±1.95, respectively. 22Rv1 cells were successfully overexpressed RP11-79H23.3 compared with the control group ( t=4.04, P<0.01). The number of 22Rv1 cell clones in the control group and RP11-79H23.3 group were 166.10 ± 18.35 and 35.03±6.98, respectively. Overexpression of RP11-79H23.3 could inhibit the proliferation of 22Rv1 cells compared with the control group ( t=6.67, P<0.01). The migration rates of 22Rv1 cells in the control group and RP11-79H23.3 group were (67.40 ± 6.29)% and (26.42 ± 6.24)%, respectively. Overexpression of RP11-79H23.3 could inhibit the migration of 22Rv1 cells compared with the control group ( t=5.71, P<0.01) .Dual-luciferase reporter gene experiment showed that RP11-79H23.3 directly binds to miR-410 ( t=6.20, P<0.01). The expression of miR-410 in 22Rv1 cells in the control group and RP11-79H23.3 group were 6.22±1.39 and 1.05±0.23, respectively. RP11-79H23.3 could inhibit the expression of miR-410 in 22Rv1 cells compared with the control group ( t=3.68, P<0.01). At the same time, RP11-79H23.3 can inhibit the transduction of the PTEN/AKT/mTOR signaling pathway in 22Rv1 cells. Conclusion:RP11-79H23.3 blocks the PTEN/AKT/mTOR signaling pathway by inhibiting the expression of miR-410, thereby inhibiting the proliferation and migration of prostate cancer 22Rv1 cells.