Indole-3-carboxaldehyde ameliorates ionizing radiation-induced hematopoietic injury by enhancing hematopoietic stem and progenitor cell quiescence.

Indole-3-carboxaldehyde (I3A), one of tryptophan metabolites derived from gut microbiota, extends the lifespan of mice after high-dose ionizing radiation exposure. Persistent myelosuppression is the most common and fatal complication for victims of nuclear accidents and patients undergoing radiotherapy, with few therapeutic options available. However, whether and how I3A protects ionizing radiation-induced hematopoietic toxicity remain unknown. In this study, we demonstrated that I3A treatment effectively ameliorated radiation-induced hematopoietic injury through accelerating peripheral blood cells recovery, promoting bone marrow cellularity restoration and enhancing functional HSPC regeneration. Additionally, I3A also suppressed intracellular reactive oxygen species production and inhibited apoptosis in irradiated HSPCs. Mechanistically, I3A treatment significantly increased HSPC quiescence, thus conferring HSPCs with resistance against radiation injury. Finally, I3A treatment could improve survival of lethally irradiated mice. Taken together, our data suggest that I3A acts as a gut microbiota-derived paracrine factor that regulates HSPC regeneration and may serve as a promising therapeutic agent for ionizing radiation-induced myelosuppression.

Remodeling Microenvironment for Endogenous Repair through Precise Modulation of Chondroitin Sulfate Proteoglycans Following Spinal Cord Injury.

The fluid-filled cystic cavity sealed by a dense scar developed following traumatic spinal cord injury (SCI) has been a major obstacle to neural regeneration and functional recovery. Here the transected lesion is bridged using a functional self-assembling peptide (F-SAP) hydrogel loaded with membrane-permeable intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), targeted at perturbing chondroitin sulfate proteoglycan (CSPG) inhibitory signaling. As compared to F-SAP hydrogel loaded with chondroitinase ABC, the F-SAP+ISP/ILP promotes a beneficial anti-inflammatory response via manipulation of microglia/macrophages infiltration and assembly of extracellular matrix (ECM) molecules into fibrotic matrix rather than scarring tissues. The remodeled ECM creates a permissive environment that supports axon regrowth and the formation of synaptic connections with neurons derived from endogenous neural stem cells. The remodeled networks contribute to functional recovery, as demonstrated by improved hind limb movements and electrophysiological properties. This work proposes a unique mechanism that ECM remodeling induced by CSPG-manipulation-based anti-inflammation can construct a permissive environment for neural regeneration, and shed light on the advancement of manipulation of cascading cellular and molecular events potential for endogenous repair of SCI.

Research on Measurement of Tooth Profile Parameters of Synchronous Belt Based on Point Cloud Data.

Accurately detecting the tooth profile parameters of the synchronous belt is crucial for the transmission's load distribution and service life. However, the existing detection methods have low efficiency, are greatly affected by the manual experience, and cannot realize automatic detection. A measurement method based on point cloud data is proposed to solve this issue. The surface space points of the synchronous belt are acquired by a line-structured light sensor, and the raw point clouds are preprocessed to remove outliers and reduce the number of points. Then, the point clouds are divided into plane and arc regions, and different methods are used for fitting. Finally, the parameters of each tooth are calculated. The experimental results show that the method has high measurement accuracy and reliable stability and can replace the original detection method to realize automatic detection.

Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study.

BACKGROUND AIMS: Stem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application. METHODS: A prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 × 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed. RESULTS: Safety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity. CONCLUSIONS: The authors' present protocol demonstrates that intrathecal administration of' allogeneic hUC-MSCs at a dose of 106 cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life.

Subarachnoid transplantation of human umbilical cord mesenchymal stem cell in rodent model with subacute incomplete spinal cord injury: Preclinical safety and efficacy study.

Functional multipotency renders human umbilical cord mesenchymal stem cell (hUC-MSC) a promising candidate for the treatment of spinal cord injury (SCI). However, its safety and efficacy have not been fully understood for clinical translation. In this study, we performed cellular, kinematic, physiological, and anatomical analyses, either in vitro or in vivo, to comprehensively evaluate the safety and efficacy associated with subarachnoid transplantation of hUC-MSCs in rats with subacute incomplete SCI. Concerning safety, hUC-MSCs were shown to have normal morphology, excellent viability, steady proliferation, typical biomarkers, stable karyotype in vitro, and no tumorigenicity both in vitro and in vivo. Following subarachnoid transplantation of hUC-MSCs in the subject rodents, the biodistribution of hUC-MSCs was restricted to the spinal cord, and no toxicity to immune system or organ function was observed. Body weight, organ weight, and the ratio of the latter upon the former between stem cell-transplanted rats and placebo-injected rats revealed no statistical differences. Regarding efficacy, hUC-MSCs could differentiate into osteoblasts, chondrocytes, adipocytes and neural progenitor cells in vitro. While in vivo studies revealed that subarachnoid transplantation of stem cells resulted in significant improvement in locomotion, earlier automatic micturition recovery and reduced lesion size, which correlated with increased regeneration of tracking fiber and reduced parenchymal inflammation. In vivo luminescence imaging showed that a few of the transplanted luciferase-labeled hUC-MSCs tended to migrate towards the lesion epicenter. Shortened latency and enhanced amplitude were also observed in both motor and sensory evoked potentials, indicating improved signal conduction in the damaged site. Immunofluorescent staining confirmed that a few of the administrated hUC-MSCs integrated into the spinal cord parenchyma and differentiated into astrocytes and oligodendrocytes, but not neurons. Moreover, decreased astrogliosis, increased remyelination, and neuron regeneration could be observed. To the best of our knowledge, this preclinical study provides detailed safety and efficacy evidence regarding intrathecal transplantation of hUC-MSCs in treating SCI for the first time and thus, supports its initiation in the following clinical trial.

Long noncoding RNA UCA1 promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells via miRNA-145-5p/SMAD5 and miRNA-124-3p/SMAD4 axis.

Long noncoding RNA (lncRNAs) UCA1 has been known to be critical for the chondrogenic differentiation of marrow mesenchymal stem cells (MSCs). In this study, we explore the effects and mechanisms of UCA1 on the promotion of chondrogenesis of MSCs. During the processes of chondrogenic differentiation of MSCs, UCA1, miRNA-145-5p or miRNA-124-3p was overexpressed into MSCs. UCA1 substantially improved chondrogenesis of MSCs. Furthermore, UCA1 obviously down-regulated the expression of miRNA-145-5p and miRNA-124-3p, which attenuated the chondrogenic differentiation of MSCs. In addition, UCA1 significantly stimulated TGF-ß pathway member SMAD5 and SMAD4, which is targeted by miRNA-145-5p and miRNA-124-3p. Collectively, these outcomes suggest that UCA1 enhances chondrogenic differentiation of MSCs via the miRNA-145-5p/SMAD5 and miRNA-124-3p/SMAD4 axis.

Alterations in the diversity and composition of mice gut microbiota by lytic or temperate gut phage treatment.

Phages, the most abundant species in the mammalian gut, have numerous advantages as biocontrol agent over antibiotics. In this study, mice were orally treated with the lytic gut phage PA13076 (group B), the temperate phage BP96115 (group C), no phage (group A), or streptomycin (group D) over 31 days. At the end of the experiment, fecal microbiota diversity and composition was determined and compared using high-throughput sequencing of the V3-V4 hyper-variable region of the 16S rRNA gene and virus-like particles (VLPs) were quantified in feces. There was high diversity and richness of microbiota in the lytic and temperate gut phage-treated mice, with the lytic gut phage causing an increased alpha diversity based on the Chao1 index (p < 0.01). However, the streptomycin treatment reduced the microbiota diversity and richness (p = 0.0299). Both phage and streptomycin treatments reduced the abundance of Bacteroidetes at the phylum level (p < 0.01) and increased the abundance of the phylum Firmicutes. Interestingly, two beneficial genera, Lactobacillus and Bifidobacterium, were enhanced by treatment with the lytic and temperate gut phage. The abundance of the genus Escherichia/Shigella was higher in mice after temperate phage administration than in the control group (p < 0.01), but lower than in the streptomycin group. Moreover, streptomycin treatment increased the abundance of the genera Klebsiella and Escherichia/Shigella (p < 0.01). In terms of the gut virome, fecal VLPs did not change significantly after phage treatment. This study showed that lytic and temperate gut phage treatment modulated the composition and diversity of gut microbiota and the lytic gut phage promoted a beneficial gut ecosystem, while the temperate phage may promote conditions enabling diseases to occur.

Hidden and overall haemorrhage following minimally invasive and open transforaminal lumbar interbody fusion.

BACKGROUND: Hidden haemorrhage has been proved to be significant in joint surgery. However, when referring to lumbar interbody fusion, it is often ignored because of its invisibility. This randomized controlled study aimed to calculate and compare hidden haemorrhage following minimally invasive and open transforaminal lumbar interbody fusion (MIS-TLIF and open TLIF). Meanwhile, its clinical significance was also analyzed. MATERIALS AND METHODS: A total of 41 patients were included in this study, then they were randomized to receive MIS-TLIF or open TLIF, 21 and 20, respectively. For each case, total volume loss of red blood cell (RBC) was calculated by Gross' formula based on perioperative haematocrit change, then perioperative visible volume loss of RBC was calculated through haemorrhage volume and weight. After deducting it from total volume loss of RBC, hidden volume loss of RBC was obtained. Absolute amount of hidden haemorrhage and its ratio upon total haemorrhage, as well as indicators assessing clinical outcomes, including visual analogue scale (VAS) for back and leg, Oswestry disability index (ODI), interbody fusion rate and complication incidence were compared and analyzed. RESULTS: Mean hidden volume loss of RBC in MIS-TLIF was significantly reduced compared with open TLIF (166.7 versus 245.6 ml). Besides, both mean total and visible volume loss of RBC in MIS-TLIF were also statistically less than those in open TLIF (355.3 versus 538.6 ml; 188.6 versus 293.0 ml). While mean ratio of hidden haemorrhage upon total haemorrhage was 46.7% for MIS-TLIF and 44.5% for open TLIF, respectively, showing no statistical significance. At one week postoperatively, more significant improvements of VAS for back and leg, as well as ODI were seen in MIS-TLIF compared with open TLIF. While at final follow-up of at least 2 years, all parameters continued to improve and revealed no statistical difference between both surgeries. Similar interbody fusion rate and complication incidence were observed in both series. CONCLUSIONS: Besides reduced visible haemorrhage and improved clinical outcomes, MIS-TLIF also owns the superiority of less hidden haemorrhage, offering another advantage over open TLIF. LEVEL OF EVIDENCE: Level II.

Effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells.

Melatonin, a lipophilic molecule mainly synthesized in the pineal gland, has properties of antioxidation, anti-inflammation, and antiapoptosis to improve neuroprotective functions. Here, we investigate effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells (iPSCs). iPSCs were induced into neural stem cells (NSCs), then further differentiated into neurons in medium with or without melatonin, melatonin receptor antagonist (Luzindole) or Phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002). Melatonin significantly promoted the number of neurospheres and cell viability. In addition, Melatonin markedly up-regulated gene and protein expression of Nestin and MAP2. However, Luzindole or LY294002 attenuated these increase. The expression of pAKT/AKT were increased by Melatonin, while Luzindole or LY294002 declined these melatonin-induced increase. These results suggest that melatonin significantly increased neural differentiation of iPSCs via activating PI3K/AKT signaling pathway through melatonin receptor.

Protective Effects and Mechanisms of Salvianolic Acid B Against H2O2-Induced Injury in Induced Pluripotent Stem Cell-Derived Neural Stem Cells.

Induced pluripotent stem cells (iPSCs) have the potential to differentiate into neural lineages. Salvianolic acid B (Sal B) is a commonly used, traditional Chinese medicine for enhancing neuroprotective effects, and has antioxidant, anti-inflammatory, and antiapoptotic properties. Here, we explore the potential mechanism of Sal B in protecting iPSC-derived neural stem cells (NSCs) against H2O2-induced injury. iPSCs were induced into NSCs, iPSC-derived NSCs were treated with 50 µM Sal B for 24.5 h and 500 µM H2O2 for 24 h. The resulting effects were examined by flow cytometry analysis, quantitative reverse-transcription polymerase chain reaction, and western blotting. Upon H2O2 exposure, Sal B significantly promoted cell viability and stabilization of the mitochondrial membrane potential. Sal B also visibly decreased the cell apoptotic ratio. In addition, Sal B markedly reduced expression of matrix metalloproteinase (MMP)-2 and -9, and phosphospecific signal transducer and activator of transcription 3 (p-STAT3), and increased the level of tissue inhibitor of metalloproteinase (TIMP)-2 in iPSC-derived NSCs induced by H2O2. These results suggest that Sal B protects iPSC-derived NSCs against H2O2-induced oxidative stress. The mechanisms of this stress tolerance may be attributed to modulation of the MMP/TIMP system and inhibition of the STAT3 signaling pathway.

Wallerian Degeneration Assessed by Multi-Modal Magnetic Resonance Imaging of Cervical Spinal Cord Is Associated With Neurological Impairment After Spinal Cord Injury.

While Wallerian degeneration (WD) is a crucial pathological process induced with spinal cord injury (SCI), its underlying mechanisms is still understudied. In this study, we aim to assess structural alterations and clinical significance of WD in the cervical cord following SCI using multi-modal magnetic resonance imaging (MRI), which combines T2*-weighted imaging and diffusion tensor imaging (DTI). T2*-weighted images allow segmentation of anatomical structures and the detection of WD on macrostructural level. DTI, on the other hand, can identify the reduction in neuroaxonal integrity by measuring the diffusion of water molecules on the microstructural level. In this prospective study, 35 SCI patients (19 paraplegic and 16 tetraplegic patients) and 12 healthy controls were recruited between July 2020 and May 2022. The hyperintensity voxels in the dorsal column was manually labeled as WD on T2*-weighted images. The mean cross-sectional area (CSA) and mean DTI indexes of WD at the C2 level were calculated and compared between groups. Correlation analysis was used to determine the associations of the magnitude of WD with lesion characteristics and clinical outcomes. Compared with controls, SCI patients showed evident hyperintensity (35/35) and decreased neuroaxonal integrity (p < 0.05) within the dorsal column at the C2 level. A higher neurological level of injury was associated with a larger mean CSA and reduction in neuroaxonal integrity within WD (p < 0.05). Smaller total and dorsal tissue bridges were related to greater mean CSA and lower fractional anisotropy values in WD (p < 0.05), respectively. Moreover, SCI participants with significantly larger CSAs and significantly lower microstructural integrity had worse sensory outcomes (p < 0.05). This comprehensive evaluation of WD can help us better understand the mechanisms of WD, monitor progression, and assess the effectiveness of therapeutic interventions after SCI.

Inhibition of MST1 ameliorates neuronal apoptosis via GSK3ß/ß-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes.

AIMS: Spinal cord injury (SCI) is a devastating neurological disease that often results in tremendous loss of motor function. Increasing evidence demonstrates that diabetes worsens outcomes for patients with SCI due to the higher levels of neuronal oxidative stress. Mammalian sterile 20-like kinase (MST1) is a key mediator of oxidative stress in the central nervous system; however, the mechanism of its action in SCI is still not clear. Here, we investigated the role of MST1 activation in induced neuronal oxidative stress in patients with both SCI and diabetes. METHODS: Diabetes was established in mice by diet induction combined with intraperitoneal injection of streptozotocin (STZ). SCI was performed at T10 level through weight dropping. Advanced glycation end products (AGEs) were applied to mimic diabetic conditions in PC12 cell line in vitro. We employed HE, Nissl staining, footprint assessment and Basso mouse scale to evaluate functional recovery after SCI. Moreover, immunoblotting, qPCR, immunofluorescence and protein-protein docking analysis were used to detect the mechanism. RESULTS: Regarding in vivo experiments, diabetes resulted in up-regulation of MST1, excessive neuronal apoptosis and weakened motor function in SCI mice. Furthermore, diabetes impeded NRF2-mediated antioxidant defense of neurons in the damaged spinal cord. Treatment with AAV-siMST1 could restore antioxidant properties of neurons to facilitate reactive oxygen species (ROS) clearance, which subsequently promoted neuronal survival to improve locomotor function recovery. In vitro model found that AGEs worsened mitochondrial dysfunction and increased cellular oxidative stress. While MST1 inhibition through the chemical inhibitor XMU-MP-1 or MST1-shRNA infection restored NRF2 nuclear accumulation and its transcription of downstream antioxidant enzymes, therefore preventing ROS generation. However, these antioxidant effects were reversed by NRF2 knockdown. Our in-depth studies showed that over-activation of MST1 in diabetes directly hindered the neuroprotective AKT1, and subsequently fostered NRF2 ubiquitination and degradation via the GSK3ß/ß-TrCP pathway. CONCLUSION: MST1 inhibition significantly restores neurological function in SCI mice with preexisting diabetes, which is largely attributed to the activation of antioxidant properties via the GSK3ß(Ser 9)/ß-TrCP/NRF2 pathway. MST1 may be a promising pharmacological target for the effective treatment of spinal cord injury patients with diabetes.

Effect of an artificial intelligence-assisted system on endoscopic diagnosis of superficial oesophageal squamous cell carcinoma and precancerous lesions: a multicentre, tandem, double-blind, randomised controlled trial.

BACKGROUND: Despite the usefulness of white light endoscopy (WLE) and non-magnified narrow-band imaging (NBI) for screening for superficial oesophageal squamous cell carcinoma and precancerous lesions, these lesions might be missed due to their subtle features and interpretation variations among endoscopists. Our team has developed an artificial intelligence (AI) system to detect superficial oesophageal squamous cell carcinoma and precancerous lesions using WLE and non-magnified NBI. We aimed to evaluate the auxiliary diagnostic performance of the AI system in a real clinical setting. METHODS: We did a multicentre, tandem, double-blind, randomised controlled trial at 12 hospitals in China. Eligible patients were aged 18 years or older and underwent sedated upper gastrointestinal endoscopy for screening, investigation of gastrointestinal symptoms, or surveillance. Patients were randomly assigned (1:1) to either the AI-first group or the routine-first group using a computerised random number generator. Patients, pathologists, and statistical analysts were masked to group assignment, whereas endoscopists and research assistants were not. The same endoscopist at each centre did tandem upper gastrointestinal endoscopy for each eligible patient on the same day. In the AI-first group, the endoscopist did the first examination with the assistance of the AI system and the second examination without it. In the routine-first group, the order of examinations was reversed. The primary outcome was the miss rate of superficial oesophageal squamous cell carcinoma and precancerous lesions, calculated on a per-lesion and per-patient basis. All analyses were done on a per-protocol basis. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100052116) and is completed. FINDINGS: Between Oct 19, 2021, and June 8, 2022, 5934 patients were randomly assigned to the AI-first group and 5912 to the routine-first group, of whom 5865 and 5850 were eligible for analysis. Per-lesion miss rates were 1·7% (2/118; 95% CI 0·0-4·0) in the AI-first group versus 6·7% (6/90; 1·5-11·8) in the routine-first group (risk ratio 0·25, 95% CI 0·06-1·08; p=0·079). Per-patient miss rates were 1·9% (2/106; 0·0-4·5) in AI-first group versus 5·1% (4/79; 0·2-9·9) in the routine-first group (0·37, 0·08-1·71; p=0·40). Bleeding after biopsy of oesophageal lesions was observed in 13 (0·2%) patients in the AI-first group and 11 (0·2%) patients in the routine-first group. No serious adverse events were reported by patients in either group. INTERPRETATION: The observed effect of AI-assisted endoscopy on the per-lesion and per-patient miss rates of superficial oesophageal squamous cell carcinoma and precancerous lesions under WLE and non-magnified NBI was consistent with substantial benefit through to a neutral or small negative effect. The effectiveness and cost-benefit of this AI system in real-world clinical settings remain to be further assessed. FUNDING: National Natural Science Foundation of China, 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University, and Chengdu Science and Technology Project. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Corticospinal circuit neuroplasticity may involve silent synapses: Implications for functional recovery facilitated by neuromodulation after spinal cord injury.

Spinal cord injury (SCI) leads to devastating physical consequences, such as severe sensorimotor dysfunction even lifetime disability, by damaging the corticospinal system. The conventional opinion that SCI is intractable due to the poor regeneration of neurons in the adult central nervous system (CNS) needs to be revisited as the CNS is capable of considerable plasticity, which underlie recovery from neural injury. Substantial spontaneous neuroplasticity has been demonstrated in the corticospinal motor circuitry following SCI. Some of these plastic changes appear to be beneficial while others are detrimental toward locomotor function recovery after SCI. The beneficial corticospinal plasticity in the spared corticospinal circuits can be harnessed therapeutically by multiple contemporary neuromodulatory approaches, especially the electrical stimulation-based modalities, in an activity-dependent manner to improve functional outcomes in post-SCI rehabilitation. Silent synapse generation and unsilencing contribute to profound neuroplasticity that is implicated in a variety of neurological disorders, thus they may be involved in the corticospinal motor circuit neuroplasticity following SCI. Exploring the underlying mechanisms of silent synapse-mediated neuroplasticity in the corticospinal motor circuitry that may be exploited by neuromodulation will inform a novel direction for optimizing therapeutic repair strategies and rehabilitative interventions in SCI patients.

A Bioinspired Injectable, Adhesive, and Self-Healing Hydrogel with Dual Hybrid Network for Neural Regeneration after Spinal Cord Injury.

Hydrogel-based regenerated scaffolds show promise as a platform for neural regeneration following spinal cord injury (SCI). Nevertheless, the persistent problem of poor mechanical strength and limited integration with the host tissue still exists. In this study, a bioinspired hydrogel with highly sophisticated features for neural regeneration after SCI is developed. The hydrogel is composed of dihydroxyphenylalanine (DOPA)-grafted chitosan and a designer peptide, offering a unique set of qualities such as being injectable, having self-healing abilities, and adhering to tissues. Compared to conventional hydrogels, this hydrogel ensures a significant promotion of immune response modulation and axon regrowth while featuring synapse formation of various neurotransmitters and myelin regeneration. Subsequently, functional recoveries are enhanced, including motor function, sensory function, and particularly bladder defect repair. These positive findings demonstrate that the hydrogel has great potential as a strategy for repairing SCI. Moreover, the versatility of this strategy goes beyond neural regeneration and holds promise for tissue regeneration in other contexts. Overall, this proposed hydrogel represents an innovative and multifaceted tool for engineering structures in the biomedical field.

Early prognostication of critical patients with spinal cord injury: A machine learning study with 1485 cases.

STUDY DESIGN: A retrospective case-series. OBJECTIVE: The study aims to use machine-learning (ML) to predict the discharge destination of spinal cord injury (SCI) patients in the intensive care unit (ICU). SUMMARY OF BACKGROUND DATA: Prognostication following SCI is vital, especially for critical patients who need intensive care. METHODS: Clinical data of patients diagnosed with SCI were extracted from a publicly available ICU database. The firstly recorded data of the included patients were used to develop a total of 98 ML classifiers, seeking to predict discharge destination (e.g. death, further medical care, home). The micro-average area under the curve (AUC) was the main indicator to assess discrimination. The best average-AUC classifier and the best death-sensitivity classifier were integrated into an ensemble classifier. The discrimination of the ensemble classifier was compared with top death-sensitivity classifiers and top average-AUC classifiers. Additionally, prediction consistency and clinical utility were also assessed. RESULTS: A total of 1485 SCI patients were included. The ensemble classifier had a micro-average AUC of 0.851, which was only slightly inferior to the best average-AUC classifier (P=0.10) The best average-AUC classifier death sensitivity was much lower than that of the ensemble classifier. The ensemble classifier had a death sensitivity of 0.452, which was inferior to top 8 death-sensitivity classifiers, whose micro-average AUC were inferior to the ensemble classifier (P<0.05). Additionally, the ensemble classifier demonstrated a comparable Brier score and superior Net benefit in the decision curve analysis, when compared to the performance of the origin classifiers. CONCLUSIONS: The ensemble classifier shows an overall superior performance in predicting discharge destination considering discrimination ability, prediction consistency and clinical utility. This classifier system may aid in the clinical management of critical SCI patients in the early phase following injury. LEVEL OF EVIDENCE: 3.

Percutaneous Transforaminal Endoscopic Discectomy Versus Microendoscopic Discectomy for Lumbar Disk Herniation: Five-year Results of a Randomized Controlled Trial.

STUDY DESIGN: A prospective randomized controlled study. OBJECTIVE: To compare the efficacy and safety between percutaneous transforaminal endoscopic discectomy (PTED) and microendoscopic discectomy (MED). SUMMARY OF BACKGROUND DATA: Two kinds of minimally invasive discectomy, PTED and MED, are now widely used for treating lumbar disk herniation (LDH). The long-term comparative results of these two techniques still remained uncertain. MATERIALS AND METHODS: In this single-center, open-label, randomized controlled trial, patients were included if they had persistent signs and symptoms of radiculopathy with corresponding imaging-confirmed LDH and were randomly allocated to PTED or MED groups. The primary outcome was the score of Oswestry Disability Index (ODI) and the secondary outcomes included the score of Medical Outcomes Study 36-Item Short-Form Health Survey bodily pain (SF36-BP) and physical function (SF36-PF), European Quality of Life-Five Dimensions (EQ-5D), Visual Analog Scales for back pain (VAS-back) and leg pain (VAS-leg). RESULTS: A total of 241 patients were accepted to enroll in our randomized controlled trial, of which 119 were randomly assigned to the PTED group, and the rest 122 were assigned to the MED group. A total of 194 out of 241 patients (80.5%) completed the five-year follow-up. PTED group was associated with shorter postoperative in-bed time and length of hospital stay. Both primary and secondary outcomes did not differ significantly between the two treatment groups at each follow-up time point. During the five-year follow-up, seven recurrent cases occurred in PTED and MED groups, respectively. CONCLUSION: Over the five-year follow-up period, PTED and MED were both efficacious in the treatment of LDH. The long-term clinical outcomes and recurrent rates were comparable between the treatment groups. PTED represents a more minimally invasive technique with the advantages of rapid recovery.

Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.

Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.

Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation.

Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder associated with progressive neurodegenerative phenotypes. Its therapeutic options are very limited. Here, we show that lithium treatment improves ataxia and feeding phenotypes, attenuates cerebellar inflammation and degeneration, and extends survival in Npc1 mouse models. In addition, lithium suppresses STING activation, SREBP2 processing to its mature form and the expression of the target genes in the Npc1 mice and in Npc1-deficient fibroblasts. Lithium impedes STING/SREBP2 transport from the ER to the Golgi, a step required for STING activation and SREBP2 processing, probably by lowering cytosolic calcium concentrations. This effect of lithium on STING/SREBP2 transport provides a mechanistic explanation for lithium's effects on Npc1 mice. Thus, this study reveals a potential therapeutic option for NP-C patients as well as a strategy to reduce active STING/SREBP2 pathway.

Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders.

Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.