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

Due to their good properties of elastic modulus, degradability and ability to promote bone repair, magnesium alloys have become a research hotspot in research of orthopedic implants. Nevertheless, most of the biomedical magnesium alloys currently available fail to meet the requirements in orthopedics because of their rapid degradation after implantation. Rare earth-magnesium alloys possess excellent corrosion resistance and are expected to become important materials as clinical orthopedic implants. This review summarizes the recent progress in studies of the physiological functions of rare earth elements, the effects of supplementation of rare earth elements on biomechanical properties and the in vitro and in vivo biocompatibility of magnesium alloys, and their contribution to tendon-bone healing, addressing also the current clinical orthopedic applications of different rare earth-magnesium alloys, challenges, and future strategies for improving these alloys.
Alloys/chemistry* ; Magnesium/chemistry* ; Metals, Rare Earth/chemistry* ; Humans ; Biocompatible Materials ; Prostheses and Implants

Objective To compare the effects of movable artificial lumbar vertebra implantation and traditional vertebral excision and fusion on the stress of adjacent intervertebral discs,so as to provide reference for the biomechanical safety of new prosthesis implantation.Methods The total lumbar vertebra CT scan data of a healthy adult were imported into the compute r-aided software Mimics 16.0 for three dimensional reconstruction.The reconstructed three dimensional model was smoothed using computer-aided software Geomagic Studio 12.0.Subsequently,meshing,parameter setting and ligaments reconstructing were completed using computer-aided software Hypermesh 13.0 and Solidworks 2013,successfully constructing the finite element model of lumbar vertebral physiology group.On the basis of the finite element model of physiological group,three vertebral bodies and two intervertebral spaces were fused and fixed,and a simplified finite element model of fusion group was constructed.The partitioned prosthesis model was inserted into the established finite element model of physiological group,replacing the L 3 vertebral body and the adjacent two intervertebral discs in the model,constructing the finite element model of non fusion group.Three finite element models were imported into computer-aided software Abaqus/Explict and loaded under six motion modes including anteflexion,dorsiflexion,left and right rotation,and left and right bending.The stress changes of adjacent intervertebral discs were calculated.Results The maximum Mises stress of the adjacent intervertebral disc in the direction of forward flexure,dorsal extension,left and right rotation and left and right lateral bending of the three finite element models was located at the site of loading and increased with the increase of loading.Under the maximum loading,the Mises stress of adjacent intervertebral discs in the above directions in the fusion group (L1-2 respectively were 0.79,0.96,1.26,1.92,1.34,1.57 MPa while L4-5 respectively were 0.52,1.13,1.50,1.74,0.94,0.87 MPa) was significantly higher than that in the physiological group (L1-2 respectively were 0.42,0.53,0.57,0.66,0.64,0.72 MPa while L4-5 respectively were 0.23,0.29,0.68,0.63,0.37,0.34 MPa).The Mises stress of adjacent intervertebral disc in the non-fusion group (L1-2 respectively were 0.38,0.57,0.75,1.02,0.87,0.90 MPa while L4-5 respectively were 0.18,0.26,0.81,0.98,0.30,0.27 MPa) was similar to that in the physiological group,although there was some difference.Conclusion Movable artificial lumbar disc prosthesis implantation can better avoid the stress increase of adjacent intervertebral discs,and its long-term implantation in the human body is expected to reduce the incidence of degeneration of adjacent intervertebral discs.

Objective To compare the clinical effectiveness and safety of transperitoneal robot assisted and retroperitoneal laparoscopic Anderson-Hynes dismembered pyeloplasty for the treatment of ureteropelvic junction obstruction. Methods From September 2008 to June 2009,six patients with primary UPJO underwent transperitoneal robot assisted dismembered pyeloplasty (TRADP) (5 males and 1 female;average age 25 yrs,range from 14-40 yrs),of whom 4 with severe hydronephrosis,2 with intermediate.According to the demographic and preoperative information,each patient in the TRADP group was matched to two corresponding patients with primary UPJO accepting retroperitoneal laparoscopic Anderson-Hynes dismembered pyeloplasty (RLADP) in the same period.The operative time,the intracorporeal suturing time,intraoperative blood loss,the duration of the urethral catheter and the drainage time,the postoperative hospital stay and the postoperative result were compared between the 2 groups.The two groups were identical with regard to gender,side of UPJO,and surgical procedure.The mean age and BMI were comparable between the TRADP and RLADP. Results Between the two groups,the operative time was ( 157 ± 20) min vs ( 127 ± 18) min ( P ＞ 0.05 ),the intracorporeal suturing time was (44 ± 6) min vs (49 ± 6 ) min ( P ＞0.05).In TRADP and RLADP groups,the intraoperative blood loss was (23 ± 8) ml vs (21 ± 17) ml ( P ＞ 0.05 ),the duration of the drain was (47 ± 10) h vs ( 161 ± 41 ) h ( P ＜ 0.01 ),the duration of the urethral catheter was (92 ±46) h vs ( 175 ±26) h (P ＜0.05),the postoperative hospital stays were (6.0 ± 0.8 ) d vs (8.0 ± 0.5) d ( P ＜ 0.01 ).The operation was successful in all cases of two groups,with no conversion to open surgery.The follow-up of 6 -32 months,with average of 20 months,showed that the clinical symptoms in the two groups disappeared and the hydronephrosis relieved. Conclusion Compared with RLADP,the TRADP has the comparable operative time,but the postoperative management for TRADP is more simple and the healing is faster,the postoperative outcomes are comparable as well.