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Background and Aims: Direct-acting antiviral agents (DAAs) achieve high sustained virologic response (SVR) in chronic hepatitis C patients; yet a proportion of patients still experience de novo liver complications after SVR. Identification of risk factors is clinically important. FIB-4 index is a useful noninvasive tool to assess fibrosis, while neutrophil-to-lymphocyte ratio (NLR) is a biomarker for systemic inflammation. Our study aimed to investigate whether the addition of NLR can increase the prediction power of pre-DAA FIB-4 for de novo liver complications after SVR., Methods: We recruited patients via The Taiwan HCV Registry (TACR) and National Health Insurance Registry Database. The inclusion criteria were patients who achieved SVR12 after DAA and were followed for at least 24 months after SVR12. Liver complications included ascites, hepatic encephalopathy, variceal bleeding, and HCC., Results: Totally 7657 patients were recruited from 2013 to 2018. Among them, 3674 patients (48.0%) had a FIB-4 value > 3.25 and 491 patients (6.4%) had a NLR >4 before DAA. After two-year of follow-up after SVR 12, 214 patients (2.8%) developed de novo liver complications. Factors associated with liver complications included male gender, diabetes mellitus, hyperlipidemia, chronic kidney disease, and pre-DAA FIB-4 >3.25 in multivariate analyses. Addition of NLR slightly did not increase the power of predicting liver complications., Conclusions: The overall incidence of de novo liver complications after SVR is low during short-term follow-up. Elevated pre-DAA FIB-4 is associated with de novo liver complications after SVR, whereas the addition of pre-DAA NLR does not increase the prediction power., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Severe spinal cord injury results in the loss of neurons in the relatively intact spinal cord below the injury area and skeletal muscle atrophy in the paralyzed limbs. These pathological processes are significant obstacles for motor function reconstruction., Objective: We performed tail nerve electrical stimulation (TNES) to activate the motor neural circuits below the injury site of the spinal cord to elucidate the regulatory mechanisms of the excitatory afferent neurons in promoting the reconstruction of locomotor function., Methods: Eight days after T10 spinal cord transection in rats, TNES was performed for 7 weeks. Behavioral scores were assessed weekly. Electrophysiological tests and double retrograde tracings were performed at week 8., Results: After 7 weeks of TNES treatment, there was restoration in innervation, the number of stem cells, and mitochondrial metabolism in the rats' hindlimb muscles. Double retrograde tracings of the tail nerve and sciatic nerve further confirmed the presence of synaptic connections between the tail nerve and central pattern generator (CPG) neurons in the lumbar spinal cord, as well as motor neurons innervating the hindlimb muscles., Conclusion: The mechanisms of TNES induced by the stimulation of primary afferent nerve fibers involves efficient activation of the motor neural circuits in the lumbosacral segment, alterations of synaptic plasticity, and the improvement of muscle and nerve regeneration, which provides the structural and functional foundation for the future use of cutting-edge biological treatment strategies to restore voluntary movement of paralyzed hindlimbs., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: Herein, we investigated whether mesenchymal stem cells (MSCs) transplantation combined with electroacupuncture (EA) treatment could decrease the proportion of proinflammatory microglia/macrophages and neurotoxic A1 reactive astrocytes and inhibit glial scar formation to enhance axonal regeneration after spinal cord injury (SCI)., Methods: Adult rats were divided into 5 groups after complete transection of the spinal cord at the T10 level: a control group, a nonacupoint EA (NA-EA) group, an EA group, an MSC group, and an MSCs+EA group. Immunofluorescence labeling, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blots were performed., Results: The results showed that MSCs+EA treatment reduced the proportion of proinflammatory M1 subtype microglia/macrophages, but increased the differentiation of anti-inflammatory M2 phenotype cells, thereby suppressing the mRNA and protein expression of proinflammatory cytokines (tumor necrosis factor-α and IL-1β) and increasing the expression of an anti-inflammatory cytokine (interleukin [IL]-10) on days 7 and 14 after SCI. The changes in expression correlated with the attenuated neurotoxic A1 reactive astrocytes and glial scar, which in turn facilitated the axonal regeneration of the injured spinal cord. In vitro, the proinflammatory cytokines increased the level of proliferation of astrocytes and increased the expression levels of C3, glial fibrillary acidic protein, and chondroitin sulfate proteoglycan. These effects were blocked by administering inhibitors of ErbB1 and signal transducer and activator of transcription 3 (STAT3) (AG1478 and AG490) and IL-10., Conclusion: These findings showed that MSCs+EA treatment synergistically regulated the microglia/macrophage subpopulation to reduce inflammation, the formation of neurotoxic A1 astrocytes, and glial scars. This was achieved by downregulating the ErbB1-STAT3 signal pathway, thereby providing a favorable microenvironment conducive to axonal regeneration after SCI.

We previously constructed a three-dimensional gelatin sponge (3D-GS) scaffold as a delivery vehicle for therapeutic cells and trophic factors in the treatment of spinal cord injury (SCI), and this study aimed to assess the biosafety and efficacy of the scaffold in a non-human primate SCI model. However, because it has only been tested in rodent and canine models, the biosafety and efficacy of the scaffold should ideally be assessed in a non-human primate SCI model before its use in the clinic. No adverse reactions were observed over 8 weeks following 3D-GS scaffold implantation into in a Macaca fascicularis with hemisected SCI. Scaffold implantation also did not add to neuroinflammatory or astroglial responses already present at the injured site, suggesting good biocompatibility. Notably, there was a significant reduction in α-smooth muscle actin (αSMA)-positive cells at the injury/implantation interface, leading to alleviation of fibrotic compression of the residual spinal cord tissue. The regenerating tissue in the scaffold showed numerous cells migrating into the implant secreting abundant extracellular matrix, resulting in a pro-regenerative microenvironment. Consequently, nerve fiber regeneration, myelination, vascularization, neurogenesis, and electrophysiological improvements were achieved. These results indicated that the 3D-GS scaffold had good histocompatibility and effectiveness in the structural repair of injured spinal cord tissue in a non-human primate and is suitable for use in the treatment of patients with SCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: After spinal cord transection injury, the inflammatory microenvironment formed at the injury site, and the cascade of effects generated by secondary injury, results in limited regeneration of injured axons and the apoptosis of neurons in the sensorimotor cortex (SMC). It is crucial to reverse these adverse processes for the recovery of voluntary movement. The mechanism of transcranial intermittent theta-burst stimulation (iTBS) as a new non-invasive neural regulation paradigm in promoting axonal regeneration and motor function repair was explored by means of a severe spinal cord transection., Methods: Rats underwent spinal cord transection and 2 mm resection of spinal cord at T10 level. Four groups were studied: Normal (no lesion), Control (lesion with no treatment), sham iTBS (lesion and no functional treatment) and experimental, exposed to transcranial iTBS, 72 h after spinal lesion. Each rat received treatment once a day for 5 days a week; behavioral tests were administered one a week. Inflammation, neuronal apoptosis, neuroprotective effects, regeneration and synaptic plasticity after spinal cord injury (SCI) were determined by immunofluorescence staining, western blotting and mRNA sequencing. For each rat, anterograde tracings were acquired from the SMC or the long descending propriospinal neurons and tested for cortical motor evoked potentials (CMEPs). Regeneration of the corticospinal tract (CST) and 5-hydroxytryptamine (5-HT) nerve fibers were analyzed 10 weeks after SCI., Results: When compared to the Control group, the iTBS group showed a reduced inflammatory response and reduced levels of neuronal apoptosis in the SMC when tested 2 weeks after treatment. Four weeks after SCI, the neuroimmune microenvironment at the injury site had improved in the iTBS group, and neuroprotective effects were evident, including the promotion of axonal regeneration and synaptic plasticity. After 8 weeks of iTBS treatment, there was a significant increase in CST regeneration in the region rostral to the site of injury. Furthermore, there was a significant increase in the number of 5-HT nerve fibers at the center of the injury site and the long descending propriospinal tract (LDPT) fibers in the region caudal to the site of injury. Moreover, CMEPs and hindlimb motor function were significantly improved., Conclusion: Neuronal activation and neural tracing further verified that iTBS had the potential to provide neuroprotective effects during the early stages of SCI and induce regeneration effects related to the descending motor pathways (CST, 5-HT and LDPT). Furthermore, our results revealed key relationships between neural pathway activation, neuroimmune regulation, neuroprotection and axonal regeneration, as well as the interaction network of key genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Wang, Chen, Wu, Yu, Yang, Xu, Guo, Ding, Li, Zeng, Ma, Gong, Wu, Zhang, Zeng and Lai.)

Following transected spinal cord injury (SCI), there is a critical need to restore nerve conduction at the injury site and activate the silent neural circuits caudal to the injury to promote the recovery of voluntary movement. In this study, we generated a rat model of SCI, constructed neural stem cell (NSC)-derived spinal cord-like tissue (SCLT), and evaluated its ability to replace injured spinal cord and repair nerve conduction in the spinal cord as a neuronal relay. The lumbosacral spinal cord was further activated with tail nerve electrical stimulation (TNES) as a synergistic electrical stimulation to better receive the neural information transmitted by the SCLT. Next, we investigated the neuromodulatory mechanism underlying the action of TNES and its synergism with SCLT in SCI repair. TNES promoted the regeneration and remyelination of axons and increased the proportion of glutamatergic neurons in SCLT to transmit brain-derived neural information more efficiently to the caudal spinal cord. TNES also increased the innervation of motor neurons to hindlimb muscle and improved the microenvironment of muscle tissue, resulting in effective prevention of hindlimb muscle atrophy and enhanced muscle mitochondrial energy metabolism. Tracing of the neural circuits of the sciatic nerve and tail nerve identified the mechanisms responsible for the synergistic effects of SCLT transplantation and TNES in activating central pattern generator (CPG) neural circuits and promoting voluntary motor function recovery in rats. The combination of SCLT and TNES is expected to provide a new breakthrough for patients with SCI to restore voluntary movement and control their muscles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis. In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15-a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1β, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: This study aimed to identify differentially expressed genes (DEGs) by transcriptome analysis to elucidate a potential mechanism by which governor vessel electroacupuncture (GV-EA) promotes neuronal survival, axonal regeneration, and functional recovery after complete transection spinal cord injury (SCI)., Methods: Sham, control, or GV-EA group adult female Sprague Dawley rats underwent a complete transection SCI protocol. SCI area RNA-seq investigated the DEGs of coding and noncoding RNAs 7 days post-SCI. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were used to classify DEGs functions, to explain a possible molecular mechanism. Immunofluorescence and BBB (Basso, Beattie, and Bresnahan) score were used to verify a GV-EA treatment effect following SCI., Results: GV-EA treatment could regulate the expression of 173 mRNA, 260 lncRNA, and 153 circRNA genes among these DEGs resulted by SCI. GO enrichment analysis showed that the DEGs were most enriched in membrane, actin binding, and regulation of Toll-like receptor signaling pathway. KEGG pathway analysis showed enriched pathways (e.g. , Toll-like receptors, MAPK, Hippo signaling). According to the ceRNA network, miR-144-3p played a regulatory role by interacting with lncRNA and circRNA. GV-EA also promoted the injured spinal cord neuron survival, axonal regeneration, and functional improvement of hind limb locomotion., Conclusion: Results of our RNA-seq suggest that post-SCI GV-EA may regulate characteristic changes in transcriptome gene expression, potential critical genes, and signaling pathways, providing clear directions for further investigation into the mechanism of GV-EA in subacute SCI treatment. Moreover, we found that GV-EA promotes neuronal survival, nerve fiber extension, and motor function recovery in subacute SCI.

This paper investigated the hardness property of the fused deposition modeling (FDM)-printed PLA samples via different process parameters of printing and raster angles. The hardness data were sampled from the flat and edge surfaces of the samples. In addition, the effect of hardness characters after the ultraviolet (UV) curing process was analyzed. Furthermore, this research found that the printing and raster angles significantly affected the hardness value of the PLA part, which slightly increased after the UV irradiation. Moreover, the results of this study will provide a reference for the field of FDM application.

Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)-approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT-1015, that allosterically activated adenosine monophosphate-activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT-1015 was shown to bind the AMPK α and β-subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT-1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia-inducible factor 1-alpha (HIF1α) and that SCT-1015-activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin-proteasome system. With declined HIF1α abundance, many glycolysis-related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT-1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT-1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The incidence and disability rate of spinal cord injury (SCI) worldwide are high, imposing a heavy burden on patients. Considerable research efforts have been directed toward identifying new strategies to effectively treat SCI. Governor Vessel electro-acupuncture (GV-EA), used in traditional Chinese medicine, combines acupuncture with modern electrical stimulation. It has been shown to improve the microenvironment of injured spinal cord (SC) by increasing levels of endogenous neurotrophic factors and reducing inflammation, thereby protecting injured neurons and promoting myelination. In addition, axons extending from transplanted stem cell-derived neurons can potentially bridge the two severed ends of tissues in a transected SC to rebuild neuronal circuits and restore motor and sensory functions. However, every single treatment approach to severe SCI has proven unsatisfactory. Combining different treatments-for example, electro-acupuncture (EA) with adult stem cell transplantation-appears to be a more promising strategy. In this review, we have summarized the recent progress over the past two decades by our team especially in the use of GV-EA for the repair of SCI. By this strategy, we have shown that EA can stimulate the nerve endings of the meningeal branch. This would elicit the dorsal root ganglion neurons to secrete excess amounts of calcitonin gene-related peptide centrally in the SC. The neuropeptide then activates the local cells to secrete neurotrophin-3 (NT-3), which mediates the survival and differentiation of donor stem cells overexpressing the NT-3 receptor, at the injury/graft site of the SC. Increased local production of NT-3 facilitates reconstruction of host neural tissue such as nerve fiber regeneration and myelination. All this events in sequence would ultimately strengthen the cortical motor-evoked potentials and restore the motor function of paralyzed limbs. The information presented herein provides a basis for future studies on the clinical application of GV-EA and adult stem cell transplantation for the treatment of SCI., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Ischemic stroke is an acute cerebrovascular disease and the third most common cause of death after ischemic heart disease. Increasing attention is being paid to finding effective treatments through traditional medicine. Thus, studying the traditional medicine for the treatment of ischemic stroke is of great importance. Traditional medicine in China includes traditional Chinese medicine (TCM) and other ethnic medicines, which is rich in variety and resources. This review first introduces the treatment mechanisms associated with ischemic stroke, such as antioxidant nitrification, antiexcitotoxic, antiapoptotic, anti-inflammatory, antiplatelet and anticoagulation mechanisms. Then, we calculated the frequency of prescription use for ischemic stroke and summarized the treatments for ischemic stroke by investigating 13 drug monographs and standards. We found 192 prescriptions from the traditional medical system for ischemic stroke, including Angong Niuhuang pill, Qishiwei Zhenzhu Pills, Ginkgo biloba leaf, and other traditional Chinese patent medicines and national medicines. There were 398 kinds of traditional medicine, including 301 kinds of plant-based medicines, 54 kinds of animal-based medicines, 28 kinds of mineral-based medicines, and 15 kinds of other medicines. We introduced the names, families, medicinal components, traditional uses, phytochemical information, and pharmacological activities of the commonly used Chinese patent medicines and TCMs. In addition, some chemicals were introduced. These medicines may be potential candidates for the treatment of ischemic stroke. This work provides a reference for the research and clinical use of new drugs for ischemic stroke., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Tissue engineering is a promising strategy to repair spinal cord injury (SCI). However, a bioscaffold with mechanical properties that match those of the pathological spinal cord tissue and a pro-regenerative matrix that allows robust neurogenesis for overcoming post-SCI scar formation has yet to be developed. Here, we report that a mechanically enhanced decellularized spinal cord (DSC) scaffold with a thin poly (lactic-co-glycolic acid) (PLGA) outer shell may fulfill the requirements for effective in situ neuroengineering after SCI. Using chemical extraction and electrospinning methods, we successfully constructed PLGA thin shell-ensheathed DSC scaffolds (PLGA-DSC scaffolds) in a way that removed major inhibitory components while preserving the permissive matrix. The DSCs exhibited good cytocompatibility with neural stem cells (NSCs) and significantly enhanced their differentiation toward neurons in vitro. Due to the mechanical reinforcement, the implanted PLGA-DSC scaffolds showed markedly increased resilience to infiltration by myofibroblasts and the deposition of dense collagen matrix, thereby creating a neurogenic niche favorable for the targeted migration, residence and neuronal differentiation of endogenous NSCs after SCI. Furthermore, PLGA-DSC presented a mild immunogenic property but prominent ability to polarize macrophages from the M1 phenotype to the M2 phenotype, leading to significant tissue regeneration and functional restoration after SCI. Taken together, the results demonstrate that the mechanically matched PLGA-DSC scaffolds show promise for effective tissue repair after SCI., (Copyright © 2021. Published by Elsevier Ltd.)

The inability of adult mammals to recover function lost after severe spinal cord injury (SCI) has been known for millennia and is mainly attributed to a failure of brain-derived nerve fiber regeneration across the lesion. Potential approaches to re-establishing locomotor function rely on neuronal relays to reconnect the segregated neural networks of the spinal cord. Intense research over the past 30 years has focused on endogenous and exogenous neuronal relays, but progress has been slow and the results often controversial. Treatments with stem cell-derived neuronal relays alone or together with functional electrical stimulation offer the possibility of improved repair of neuronal networks. In this review, we focus on approaches to recovery of motor function in paralyzed patients after severe SCI based on novel therapies such as implantation of stem cell-derived neuronal relays and functional electrical stimulation. Recent research progress offers hope that SCI patients will one day be able to recover motor function and sensory perception., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury. However, achieving good outcome remains difficult. Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites. However, it has not been reported whether this material promotes axonal regeneration in vivo. In the present study, a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells. This functional scaffold promoted the directional growth and remyelination of regenerating axons. In vitro, the porcine decellularized optic nerve contained many straight, longitudinal channels with a uniform distribution, and microscopic pores were present in the channel wall. The spatial micro topological structure and extracellular matrix were conducive to the adhesion, survival and migration of neural stem cells. The scaffold promoted the directional growth of dorsal root ganglion neurites, and showed strong potential for myelin regeneration. Furthermore, we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo. Four weeks later, the regenerating axons grew straight, the myelin sheath in the injured/transplanted area recovered its structure, and simultaneously, the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced. Together, these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration. All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2019-B034) on February 28, 2019., Competing Interests: None

Directional axon regeneration and remyelination are crucial for repair of spinal cord injury (SCI), but existing treatments do not effectively promote those processes. Here, we propose a strategy for construction of niche-specific spinal white matter-like tissue (WMLT) using decellularized optic nerve (DON) loaded with neurotrophin-3 (NT-3)-overexpressing oligodendrocyte precursor cells. A rat model with a white matter defect in the dorsal spinal cord of the T10 segment was used. The WMLT transplantation group showed significant improvement in coordinated motor functions compared with the control groups. WMLT transplants integrated well with host spinal cord white matter, effectively addressing several barriers to directional axonal regeneration and myelination during SCI repair. In WMLT, laminin was found to promote development of oligodendroglial lineage (OL) cells by binding to laminin receptors. Interestingly, laminin could also guide linear axon regeneration via interactions with specific integrins on the axon surface. The WMLT developed here utilizes the unique microstructure and bioactive matrix of DON to create a niche rich in laminin, NT-3 and OL cells to achieve significant structural repair of SCI. Our protocol can help to promote research on repair of nerve injury and construction of neural tissues and organoids that form specific cell niches., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

Additive manufacturing (AM) has the advantages of providing materials with lightweight microporous structures and customized features, and being environmentally safe. It is widely used in medical sciences, the aerospace industry, biological research, engineering applications, and other fields. Among the many additive manufacturing methods, fused deposition modeling (FDM) is relatively low-cost, wastes less raw material and has a lower technical threshold. This paper presents a study on 3D printing based on FDM by changing two printing parameters, namely the printing temperature and filling percentage. The produced polylactic acid (PLA) material was analyzed through tensile and Shore D hardness tests and the differences in mechanical properties before and after the UV curing process were analyzed. The results show that increasing the filling percentage or increasing the printing temperature can effectively improve the tensile Young's modulus, ultimate tensile strength, elongation, and Shore hardness of the material. The UV curing process could enhance the rigidity and hardness of the material significantly but reduced the strength and toughness of the material. These findings could benefit researchers studying FDM with the goal of achieving sustainable manufactured materials.

In order to optimize the efficiency of the Fused deposition modeling (FDM) process, this study used polylactic acid (PLA) material under different parameters (the printing angle and the raster angle) to fabricate specimens and to explore its tensile properties. The effect of the ultraviolet (UV) curing process on PLA materials was also investigated. The results showed that the printing and raster angles have a high impact on the tensile properties of PLA materials. The UV curing process enhanced the brittleness and reduced the elongation of PLA material. Different effects were observed on tensile strength and modulus of specimens printed with different parameters after UV curing. The above results will be a great help for researchers who are working to achieve sustainability of PLA materials and FDM technology.

Aims: This study was aimed to investigate whether electroacupuncture (EA) would increase the secretion of neurotrophin-3 (NT-3) from injured spinal cord tissue, and, if so, whether the increased NT-3 would promote the survival, differentiation, and migration of grafted tyrosine kinase C (TrkC)-modified mesenchymal stem cell (MSC)-derived neural network cells. We next sought to determine if the latter would integrate with the host spinal cord neural circuit to improve the neurological function of injured spinal cord., Methods: After NT-3-modified Schwann cells (SCs) and TrkC-modified MSCs were co-cultured in a gelatin sponge scaffold for 14 days, the MSCs differentiated into neuron-like cells that formed a MSC-derived neural network (MN) implant. On this basis, we combined the MN implantation with EA in a rat model of spinal cord injury (SCI) and performed immunohistochemical staining, neural tracing, electrophysiology, and behavioral testing after 8 weeks., Results: Electroacupuncture application enhanced the production of endogenous NT-3 in damaged spinal cord tissues. The increase in local NT-3 production promoted the survival, migration, and maintenance of the grafted MN, which expressed NT-3 high-affinity TrkC. The combination of MN implantation and EA application improved cortical motor-evoked potential relay and facilitated the locomotor performance of the paralyzed hindlimb compared with those of controls. These results suggest that the MN was better integrated into the host spinal cord neural network after EA treatment compared with control treatment., Conclusions: Electroacupuncture as an adjuvant therapy for TrkC-modified MSC-derived MN, acted by increasing the local production of NT-3, which accelerated neural network reconstruction and restoration of spinal cord function following SCI., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Fused Deposition Modeling (FDM) can be used to manufacture any complex geometry and internal structures, and it has been widely applied in many industries, such as the biomedical, manufacturing, aerospace, automobile, industrial, and building industries. The purpose of this research is to characterize the polylactic acid (PLA) and polyethylene terephthalate glycol (PETG) materials of FDM under four loading conditions (tension, compression, bending, and thermal deformation), in order to obtain data regarding different printing temperatures and speeds. The results indicated that PLA and PETG materials exhibit an obvious tensile and compression asymmetry. It was observed that the mechanical properties (tension, compression, and bending) of PLA and PETG are increased at higher printing temperatures, and that the effect of speed on PLA and PETG shows different results. In addition, the mechanical properties of PLA are greater than those of PETG, but the thermal deformation is the opposite. The above results will be a great help for researchers who are working with polymers and FDM technology to achieve sustainability.

The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction, which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury. Herein, we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge (NF-GS) scaffold might improve tissue repair efficacy. To test this, we engineered tropomyosin receptor kinase C (TrkC) -modified neural stem cell (NSC)-derived neural network tissue with robust viability within an NF-GS scaffold. When NSCs were genetically modified to overexpress TrkC, the NT-3 receptor, a functional neuronal population dominated the neural network tissue. The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord. Additionally, host nerve fibers regenerated into the graft, making synaptic connections with the donor neurons. Accordingly, motor function recovery was significantly improved in rats with spinal cord injury (SCI) that received TrkC -modified NSC-derived neural network tissue transplantation. Together, the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI., Competing Interests: The authors declare no conflict of interest.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Spinal cord injury (SCI) invariably results in neuronal death and failure of axonal regeneration. This is attributed mainly to the hostile microenvironment and the poor intrinsic regrowth capacity of the injured spinal neurons. We have reported previously that electro-acupuncture on Governor Vessel acupoints (GV-EA) can promote neuronal survival and axonal regeneration of injured spinal cord. However, the underlying mechanism for this has remained uncertain. The present study aimed to explore the neural afferent pathway of GV-EA stimulation and the possible mechanism by which GV-EA can activate the intrinsic growth ability of injured spinal neurons. By cholera toxin B (CTB) retrograde labeling, immunostaining, and enzyme-linked immunosorbent assay (ELISA), we showed here that GV-EA could stimulate the spinal nerve branches of the dorsal root ganglion cells. This would then increase the release of calcitonin gene-related peptide (CGRP) from the afferent terminals in the spinal cord. It is of note that the effect was abrogated after dorsal rhizotomy. Additionally, both in vivo and in vitro results showed that CGRP would act on the post-synaptic spinal cord neurons and triggered the synthesis and secretion of neurotrophin-3 (NT-3) by activating the calcitonin gene-related peptide (CGRP)/ receptor activity-modifying protein (RAMP)1/calcium/calmodulin-dependent protein kinase (αCaMKII) pathway. Remarkably, the observed effect was prevented by the dorsal rhizotomy and the blockers of the CGRP/RAMP1/αCaMKII pathway. More importantly, increase in NT-3 promoted the survival, axonal regrowth, and synaptic maintenance of spinal cord neurons in the injured spinal cord. Therefore, it is concluded that increase in NT-3 production is one of the mechanisms by which GV-EA can activate the intrinsic growth ability of spinal neurons after SCI. The experimental results have reinforced the theoretical basis of GV-EA for its clinical efficacy in patients with SCI.

Krypton (Kr) and xenon (Xe) are nowadays widely applied in technical and industrial fields. Separating and collecting highly pure Xe from nuclear facilities are necessary and urgent. However, the technology is limited due to the inert nature of Xe and other interferential factors. In this work, a calcium-based metal-organic framework, Ca-SINAP-1 , which comprises a three-dimensional microporous framework with a suitable pore width, was researched for xenon and krypton separation through both experimental and theoretical methods. Ca-SINAP-1 , synthesized in solvothermal and gamma ray conditions, features accessible open-metal sites, exhibits a high Xe/Kr selectivity of 10.32, and owns a Xe adsorption capacity of 2.87 mmol/g at room temperature (1.0 bar). Particularly, its excellent chemical stability (from pH 2 to 13) and thermal stability (up to 550 °C), as well as radiation-resistance (up to 400 kGy β irradiations), render this material a promising candidate for radioactive inert gases treatment.

Allogeneic or homologous tissue transplantation is an effective strategy to repair tissue injury. However, the central nervous tissues like the brain, spinal cord, and optic nerve are not ideal materials for nervous tissue regeneration due to the excessive axonal inhibitor cues in their microenvironments. In the present study, we found that decellularization optimizes the function of the adult optic nerve in supporting the oriented outgrowth of dorsal root ganglion (DRG) neurites. The neurites growing on the decellularized optic nerve (DON) showed longer extension distances than those growing on the normal optic nerve (ON). Neurite branching was also significantly increased on the DON compared to on the ON. Decellularization selectively removed some axon-inhibitory molecules such as myelin-associated glycoprotein (basically not detected in DON) and chondroitin sulfate proteoglycans (detected in DON at a level less than 0.3 fold that in ON) and preserved some axon-promoted extracellular matrix (ECM) proteins, including collagen IV and laminin (detected at levels 6.0-fold higher in DON than in ON). Furthermore, collagen IV and laminin were shown to be preserved in DON, and their binding activities with integrin α1 were retained to promote the extension of DRG neurites. Together, the findings provide a feasible way to optimize the axon-inhibited microenvironment of central nervous tissues and establish a theoretical basis for the application of DON scaffolds in repairing central nervous injury., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chip-based optical beam scanners hold promise for future compact high-speed light detection and ranging (LIDAR) systems. Many of the demonstrated chip-based optical beam scanners are designed based on diffraction-based waveguide gratings as on-chip antennas. The waveguide grating antenna, however, only provides a typical field-of-view (FOV) of roughly 10° by tuning the input light wavelength. In this paper, polarization-division and spatial-division multiplexed nanoantenna arrays are proposed to expand the FOV of on-chip antennas. The proposed device, based on silicon-on-insulator (SOI) platform, consists of three nanoantenna groups which are densely packed and fed by a common silicon nanostrip. It is demonstrated that the combination of the optical mode-multiplexing technique and the antenna engineering allows independent controls over the interactions between multiple nanoantenna groups and the waveguide. By proper engineering of the antenna dimensions, the proposed device achieves a FOV of over 40° within a 100 nm wavelength tuning range, almost tripling that of the conventional waveguide grating antenna.

Background: To evaluate the effectiveness of diphenhydramine, an antihistamine with anti-muscarinic properties, for prevention of postoperative catheter-related bladder discomfort (CRBD)., Methods: Ninety-six ASA physical status I and II adult female patients (20-60 years) scheduled for elective gynecologic laparoscopic surgery were included. Patients were randomized into two groups of 48 patients each. All patients received a detailed preoperative explanation of the possible consequences of CRBD. The control group received normal saline 2 ml, whereas the diphenhydramine group received diphenhydramine 30 mg intravenously after induction of general anesthesia. Then, all patients were catheterized with a 14F Foley catheter and the balloon was inflated with 10 ml of distilled water. All patients who complained of CRBD in the postoperative room were appeased with nursing. Ketorolac 30 mg was used as the rescue drug on patients' request or when the patient was evaluated as having moderate or severe CRBD. Bladder discomfort and its severity were assessed at 1, 2 and 6 h postoperatively. The severity of CRBD was graded as none, mild, moderate and severe. Adverse effects of diphenhydramine such as sedation, dry mouth or GI upset were recorded., Results: The incidence of CRBD was lower in the diphenhydramine group compared with the control group at 2 h (34.8 vs. 58.7%, p = 0.02) and 6 h (23.9 vs. 56.5%, p < 0.01) postoperatively. Diphenhydramine treatment also reduced the severity of CRBD at 6 h postoperatively (p = 0.01). Moreover, the request for rescue for CRBD was lower in diphenhydramine group at 2 h (8.7 vs. 26.1%, p = 0.03). There were no significant differences in side effects, such as sedation, dry mouth or gastrointestinal upset between the two groups (p > 0.05)., Conclusion: Prophylactic diphenhydramine 30 mg at induction of general anesthesia reduced the incidence and severity of postoperative bladder discomfort without significant side effects in patients receiving gynecologic laparoscopic surgery.

Leucine-rich repeat and immunoglobulin domain-containing protein 1 (LINGO-1) is a transmembrane protein that negatively regulates neural regeneration in the central nervous system. LINGO-1 expression is up-regulated after central nerve injury, and is accompanied by cell death. Both LINGO-1 and cell death in the injury microenvironment are thought to limit neural regeneration, but the relationship between LINGO-1 and cell death has not been characterized. To investigate whether LINGO-1 deletion improves the spinal cord microenvironment after spinal cord injury (SCI) and contributes to cell survival, we generated LINGO-1 knockout (KO) mice. These mice and wild-type control mice were subjected to spinal cord transection. Fourteen days after spinal cord transection, cell apoptosis, inflammation, glial scar, and growth of nerve fibers were evaluated by immunostaining. The results showed that LINGO-1 KO mice demonstrated a profound reduction in expression of caspase-3, transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL), ionized calcium binding adapter molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and chondroitin sulfate proteoglycans (CSPGs) compared to controls. In contrast, expression of neurofilament (NF) at the SCI site in LINGO-1 KO mice was markedly increased compared to that in wild-type mice. These results suggested that LINGO-1 plays a critical role in the injury microenvironment in processes such as cell death, inflammatory response, and glial scar formation. Importantly, LINGO-1 deletion and a positive microenvironment may exert synergistic effects to promote nerve fiber regeneration. Therefore, inhibition of LINGO-1 may be a therapeutic strategy to promote neural regeneration following SCI., (Published by Elsevier Inc.)

Tissue engineering produces constructs with defined functions for the targeted treatment of damaged tissue. A complete spinal cord injury (SCI) model is generated in canines to test whether in vitro constructed neural network (NN) tissues can relay the excitatory signal across the lesion gap to the caudal spinal cord. Established protocols are used to construct neural stem cell (NSC)-derived NN tissue characterized by a predominantly neuronal population with robust trans-synaptic activities and myelination. The NN tissue is implanted into the gap immediately following complete transection SCI of canines at the T10 spinal cord segment. The data show significant motor recovery of paralyzed pelvic limbs, as evaluated by Olby scoring and cortical motor evoked potential (CMEP) detection. The NN tissue survives in the lesion area with neuronal phenotype maintenance, improves descending and ascending nerve fiber regeneration, and synaptic integration with host neural circuits that allow it to serve as a neuronal relay to transmit excitatory electrical signal across the injured area to the caudal spinal cord. These results suggest that tissue-engineered NN grafts can relay the excitatory signal in the completely transected canine spinal cord, providing a promising strategy for SCI treatment in large animals, including humans., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported., Objective: To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan., Methods: We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan., Results: Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P <.05). Compared with the healthy population, the patients with HbH disease exhibited short body length, low body weight, and low body mass index (BMI)., Conclusions: Patients with nondeletional HbH disease had lower Hb levels and a higher requirement for splenectomy and iron-chelation therapy than did those with deletional HbH disease. Also, growth status was compromised in patients with HbH disease., (© American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vertical-emitting optical couplers that convert in-plane guided light to out-of-plane emission are crucial elements for future photonic integrated circuits. However, traditional vertical-coupling elements, such as grating couplers, by default radiate light in both upward and downward directions, leading to a significant reduction of device efficiency. In this paper, we propose to solve this problem using a novel nanopatch antenna array, inspired by patch antenna theories commonly deployed in microwave circuits. The proposed nanopatch array features an up-to-down emission directionality up to 12.91 dBc and a wide operating bandwidth of over 400 nm simultaneously. Compared with a typical waveguide grating antenna, our design shows a significantly higher free-space gain of 24.27 dBi. The unidirectional, efficient, and broadband antenna arrays presented here are promising for a range of integrated photonics applications, including inter-chip photonic interconnects, light ranging and detection, optical communications, and biological imaging.

The hostile environment of an injured spinal cord makes it challenging to achieve higher viability in a grafted tissue-engineered neural network used to reconstruct the spinal cord circuit. Here, we investigate whether cell survival and synaptic transmission within an NT-3 and TRKC gene-overexpressing neural stem cell-derived neural network scaffold (NN) transplanted into transected spinal cord could be promoted by electroacupuncture (EA) through improving the microenvironment. Our results showed that EA facilitated the cell survival, neuronal differentiation, and synapse formation of a transplanted NN. Pseudorabies virus tracing demonstrated that EA strengthened synaptic integration of the transplanted NN with the host neural circuit. The combination therapy also promoted axonal regeneration, spinal conductivity, and functional recovery. The findings highlight EA as a potential and safe supplementary therapeutic strategy to reinforce the survival and synaptogenesis of a transplanted NN as a neuronal relay to bridge the two severed ends of an injured spinal cord., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: The aim of palliative care is to improve quality of life for patients with serious illnesses by treating their symptoms and adverse effects. Hospice care also aims for this for patients with a life expectancy of six months or less. When conventional therapies do not provide adequate symptom management or produce their own adverse effects, patients, families, and caregivers may prefer complementary or alternative approaches in their care., Objectives: The objectives of this study were to evaluate the available evidence on the use of complementary or alternative medicine (CAM) in hospice and palliative care and to summarize their potential benefits., Methods: A defined search strategy was used in reviewing literature from major databases. Searches were conducted using base terms and the symptom in question. Symptoms included anxiety, pain, dyspnea, cough, fatigue, insomnia, nausea, and vomiting. Studies were selected for further evaluation based on relevancy and study type. References of systematic reviews were also assessed. After evaluation using quality assessment tools, findings were summarized and the review was structured based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: Out of 4682 studies, 17 were identified for further evaluation. Therapies included acupressure, acupuncture, aromatherapy massage, breathing, hypnotherapy, massage, meditation, music therapy, reflexology, and reiki. Many studies demonstrated a short-term benefit in symptom improvement from baseline with CAM, although a significant benefit was not found between groups., Conclusion: CAM may provide a limited short-term benefit in patients with symptom burden. Additional studies are needed to clarify the potential value of CAM in the hospice or palliative setting., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

We have reported previously that bone marrow mesenchymal stem cell (MSC)-derived neural network scaffold not only survived in the injury/graft site of spinal cord but also served as a "neuronal relay" that was capable of improving the limb motor function in a complete spinal cord injury (SCI) rat model. It remained to be explored whether such a strategy was effective for repairing the large spinal cord tissue loss as well as restoring motor function in larger animals. We have therefore extended in this study to construct a canine MSC-derived neural network tissue in vitro with the aim to evaluate its efficacy in treating adult beagle dog subjected to a complete transection of the spinal cord. The results showed that after co-culturing with neurotropin-3 overexpressing Schwann cells in a gelatin sponge scaffold for 14 days, TrkC overexpressing MSCs differentiated into neuron-like cells. In the latter, some cells appeared to make contacts with each other through synapse-like structures with trans-synaptic electrical activities. Remarkably, the SCI canines receiving the transplantation of the MSC-derived neural network tissue demonstrated a gradual restoration of paralyzed limb motor function, along with improved electrophysiological presentation when compared with the control group. Magnetic resonance imaging and diffusion tensor imaging showed that the canines receiving the MSC-derived neural network tissue exhibited robust nerve tract regeneration in the injury/graft site. Histological analysis showed that some of the MSC-derived neuron-like cells had survived in the injury/graft site up to 6.5 months. Implantation of MSC-derived neural network tissue significantly improved the microenvironment of the injury/graft site. It is noteworthy that a variable number of them had integrated with the regenerating corticospinal tract nerve fibers and 5-HT nerve fibers through formation of synapse-like contacts. The results suggest that the transplanted MSC-derived neural network tissue may serve as a structural and functional "neuronal relay" to restore the paralyzed limb motor function in the canine with complete SCI., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

CSPGs are components of the extracellular matrix in the nervous system, where they serve as cues for axon guidance during development. After a peripheral nerve injury, CSPGs switch roles and become axon inhibitors and become diffusely distributed at the injury site. To investigate whether the spatial distribution of CSPGs affects their role, we combined in vitro DRG cultures with CSPG stripe or coverage assays to simulate the effect of a patterned substrate or dispersive distribution of CSPGs on growing neurites. We observed neurite steering at linear CSPG interfaces and neurite inhibition when diffused CSPGs covered the distal but not the proximal segment of the neurite. The repellent and inhibitory effects of CSPGs on neurite outgrowth were associated with the disappearance of focal actin filaments on growth cones. The application of an actin polymerization inducer, jasplakinolide, allowed neurites to break through the CSPG boundary and grow on CSPG-coated surfaces. The results of our study collectively reveal a novel mechanism that explains how the spatial distribution of CSPGs determines whether they act as a cue for axon guidance or as an axon-inhibiting factor. Increasing our understanding of this issue may promote the development of novel therapeutic strategies that regulate the spatial distributions of CSPGs to use them as an axon guidance cue., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) normally results in cell death, scarring, cavitation, inhibitory molecules release, etc., which are regarded as a huge obstacle to reconnect the injured neuronal circuits because of the lack of effective stimulus. In this study, a functional gelatin sponge scaffold was used to inhibit local inflammation, enhance nerve fiber regeneration, and improve neural conduction in the canine. This scaffold had good porosity and modified with neurotrophin-3 (NT-3)/fibroin complex, which showed sustained release in vitro. After the scaffold was transplanted into canine spinal cord hemisection model, hindlimb movement, and neural conduction were improved evidently. Migrating host cells, newly formed neurons with associated synaptic structures together with functional blood vessels with intact endothelium in the regenerating tissue were identified. Taken together, the results demonstrated that using bioactive scaffold could establish effective microenvironment stimuli for endogenous regeneration, providing a potential and practical strategy for treatment of spinal cord injury. © 2018 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2158-2170, 2018., (© 2018 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc.)

Tissue engineering-based neural construction holds promise in providing organoids with defined differentiation and therapeutic potentials. Here, a bioengineered transplantable spinal cord-like tissue (SCLT) is assembled in vitro by simulating the white matter and gray matter composition of the spinal cord using neural stem cell-based tissue engineering technique. Whether the organoid would execute targeted repair in injured spinal cord is evaluated. The integrated SCLT, assembled by white matter-like tissue (WMLT) module and gray matter-like tissue (GMLT) module, shares architectural, phenotypic, and functional similarities to the adult rat spinal cord. Organotypic coculturing with the dorsal root ganglion or muscle cells shows that the SCLT embraces spinal cord organogenesis potentials to establish connections with the targets, respectively. Transplantation of the SCLT into the transected spinal cord results in a significant motor function recovery of the paralyzed hind limbs in rats. Additionally, targeted spinal cord tissue repair is achieved by the modular design of SCLT, as evidenced by an increased remyelination in the WMLT area and an enlarged innervation in the GMLT area. More importantly, the pro-regeneration milieu facilitates the formation of a neuronal relay by the donor neurons, allowing the conduction of descending and ascending neural inputs.

The functional multipotency enables mesenchymal stem cells (MSCs) promising translational potentials in treating spinal cord injury (SCI). Yet the fate of MSCs grafted into the injured spinal cord has not been fully elucidated even in preclinical studies, rendering concerns of their safety and genuine efficacy. Here we used a rat spinal cord transection model to evaluate the cell fate of allograft bone marrow derived MSCs. With the application of immunosuppressant, donor cells, delivered by biocompatible scaffold, survived up to 8 weeks post-grafting. Discernible tubes formed by MSCs were observed beginning 2 weeks after transplantation and they dominated the morphological features of implanted MSCs at 8 weeks post-grafting. The results of immunocytochemistry and transmission electron microscopy displayed the formation of perineurium-like sheath by donor cells, which, in a manner comparable to the perineurium in peripheral nerve, enwrapped host myelins and axons. The MSC-derived perineurium-like sheath secreted a group of trophic factors and permissive extracellular matrix, and served as a physical and chemical barrier to insulate the inner nerve fibers from ambient oxidative insults by the secretion of soluble antioxidant, superoxide dismutase-3 (SOD3). As a result, many intact regenerating axons were preserved in the injury/graft site following the forming of perineurium-like sheath. A parallel study utilizing a good manufacturing practice (GMP) grade human umbilical cord-derived MSCs or allogenic MSCs in an acute contusive/compressive SCI model exhibited a similar perineurium-like sheath formed by surviving donor cells in rat spinal cord at 3 weeks post-grafting. The present study for the first time provides an unambiguous morphological evidence of perineurium-like sheath formed by transplanted MSCs and a novel therapeutic mechanism of MSCs in treating SCI., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This corrects the article DOI: 10.1038/sc.2016.36.

Background/aims: Hepatitis C virus (HCV) prevails in patients with thalassemia. We aimed to investigate the efficacy, safety, and impact on red blood cells (RBC) transfusion demand of pegylated interferon (Peg-IFN)/ribavirin therapy in thalassemic patients with HCV., Methods: This retrospective study included 18 thalassemic patients (16 with HCV-1b, one HCV-1b/2b, and one HCV-2b) and 54 consecutive sex- and genotype-matched controls. Patients with HCV-2, or HCV-1 or mixed HCV-1/2 with lower viral loads plus rapid virological response (RVR) received 24-week Peg-IFN/ribavirin; whereas HCV-1 or mixed HCV-1/2 with higher viral loads or without RVR received 48-week regimens., Results: The rates of RVR, complete early virological response, and sustained virological response (SVR) in thalassemic patients were 72.2% (13/18), 94.1% (16/17), and 77.8% (14/18), which resembled those of controls (63.0%, 94.4%, and 81.5%, respectively). RVR was the only significant factor associated with SVR in thalassemic group, and was the strongest predictor for SVR among both groups (OR/95% CI = 14.7/2.20-98.6), followed by male gender and lower viral loads. More proportion of interleukin-28B-TT carriage were observed among thalassemic patients with SVR versus non-SVR (78.6% vs. 50.0%). Thalassemic patients experienced significantly less 80/80/80 adherence, more ribavirin reduction and serious adverse events than controls. Notably, there was a decreased post-treatment RBC transfusion demand versus baseline in thalassemic patients with SVR (5.21 vs. 5.64 units/month, p = 0.05), but not in those without SVR (6.33 vs. 6.56 units/month, p = 0.54)., Conclusion: Peg-IFN/ribavirin was effective and tolerable for thalassemic HCV patients. Successful antiviral therapy might have extra benefit of reducing the post-treatment transfusion demand., (Copyright © 2017. Published by Elsevier B.V.)

In our previous study, we found that the edible alcohol extract of the root of the medicinal plant Rhodiola crenulata (RCE) improved spatial cognition in a rat model of Alzheimer's disease. Another study from our laboratory showed that RCE enhanced neural cell proliferation in the dentate gyrus of the hippocampus and prevented damage to hippocampal neurons in a rat model of chronic stress-induced depression. However, the mechanisms underlying the neuroprotective effects of RCE are unclear. In the present study, we investigated the anti-apoptotic effect of RCE and its neuroprotective mechanism of action in a rat model of Alzheimer's disease established by intracerebroventricular injection of streptozotocin. The rats were pre-administered RCE at doses of 1.5, 3.0 or 6.0 g/kg for 21 days before model establishment. ATP and cytochrome c oxidase levels were significantly decreased in rats with Alzheimer's disease. Furthermore, neuronal injury was obvious in the hippocampus, with the presence of a large number of apoptotic neurons. In comparison, in rats given RCE pretreatment, ATP and cytochrome c oxidase levels were markedly increased, the number of apoptotic neurons was reduced, and mitochondrial injury was mitigated. The 3.0 g/kg dose of RCE had the optimal effect. These findings suggest that pretreatment with RCE prevents mitochondrial dysfunction and protects hippocampal neurons from apoptosis in rats with Alzheimer's disease., Competing Interests: None declared.

Optical phased arrays have been demonstrated to enable a variety of applications ranging from high-speed on-chip communications to vertical surface emitting lasers. Despite the prosperities of the researches on optical phased arrays, presently, the reported designs of optical phased arrays are based on silicon photonics while plasmonic-based optical phased arrays have not been demonstrated yet. In this paper, a passive plasmonic optical phased array is proposed and experimentally demonstrated. The beam of the proposed plasmonic optical phased array is steerable in the far-field area and a high directivity can be achieved. In addition, radio frequency phased array theory is demonstrated to be applicable to the description of the coupling conditions of the delocalized surface plasmons in optical phased arrays and thus the gap between the phased arrays at two distinctly different wavelengths can be bridged. The potential applications of the proposed plasmonic phased arrays include on-chip optical wireless nanolinks, optical interconnections and integrated plasmonic lasers.

Background/aims: Transfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan., Methods: A total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance., Results: The seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07-1.18, P<0.001), serum alanine aminotransferase (ALT) (OR/CI: 1.04/1.02-1.06, P<0.001) and platelet counts (OR/CI: 0.995/0.991-0.998, P = 0.002). Age was the only factor independently associated with HBsAg seropositivity (OR/CI: 1.08/1.02-1.14.4, P = 0.007). Compared to patients born before 1992, the seroprevalence of HCV among thalassemic patients decreased dramatically in those born after 1992 (46.0% vs. 11.8%, p = 0.012). The seroprevalence of HCV among hemophilic patients also decreased significantly when comparing patients born before 1987 to those born after 1987 (79.5% vs. 11.5%, p<0.001). Similarly, the seroprevalence of HBV decreased significantly in the post-vaccination cohort compared to its counterpart (13.1%, vs. 1.3%, p = 0.005). The spontaneous clearance of HCV was observed in 25.4% (15/59) of patients, and ALT was the only factor associated with it (OR/CI 0.98/0.96-1.00, P = 0.02)., Conclusions: Both HBV and HCV infections are prevalent among transfusion-dependent thalassemic and hemophilic patients in Taiwan. Nevertheless, seroprevalence decreased significantly and dramatically for HCV after universal blood screening and for HBV after implementation of a universal mass vaccination program.

Objectives: In spinal cord demyelination, some oligodendrocyte precursor cells (OPCs) remain in the demyelinated region but have a reduced capacity to differentiate into oligodendrocytes. This study investigated whether 'Governor Vessel' (GV) electroacupuncture (EA) would promote the differentiation of endogenous OPCs into oligodendrocytes by activating the retinoid X receptor γ (RXR-γ)-mediated signalling pathway., Methods: Adult rats were microinjected with ethidium bromide (EB) into the T10 spinal cord to establish a model of spinal cord demyelination. EB-injected rats remained untreated (EB group, n=26) or received EA treatment (EB+EA group, n=26). A control group (n=26) was also included that underwent dural exposure without EB injection. After euthanasia at 7 days (n=5 per group), 15 days (n=8 per group) or 30 days (n=13 per group), protein expression of RXR-γ in the demyelinated spinal cord was evaluated by immunohistochemistry and Western blotting. In addition, OPCs derived from rat embryonic spinal cord were cultured in vitro, and exogenous 9-cis-RA (retinoic acid) and RXR-γ antagonist HX531 were administered to determine whether RA could activate RXR-γ and promote OPC differentiation., Results: EA was found to increase the numbers of both OPCs and oligodendrocytes expressing RXR-γ and RALDH2, and promote remyelination in the remyelinated spinal cord. Exogenous 9-cis-RA enhanced the differentiation of OPCs into mature oligodendrocytes by activating RXR-γ., Conclusions: The results suggest that EA may activate RXR signalling to promote the differentiation of OPCs into oligodendrocytes in spinal cord demyelination., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Spinal cord injury (SCI) often results in death of spinal neurons and atrophy of muscles which they govern. Thus, following SCI, reorganizing the lumbar spinal sensorimotor pathways is crucial to alleviate muscle atrophy. Tail nerve electrical stimulation (TANES) has been shown to activate the central pattern generator (CPG) and improve the locomotion recovery of spinal contused rats. Electroacupuncture (EA) is a traditional Chinese medical practice which has been proven to have a neural protective effect. Here, we examined the effects of TANES and EA on lumbar motor neurons and hindlimb muscle in spinal transected rats, respectively. From the third day postsurgery, rats in the TANES group were treated 5 times a week and those in the EA group were treated once every other day. Four weeks later, both TANES and EA showed a significant impact in promoting survival of lumbar motor neurons and expression of choline acetyltransferase (ChAT) and ameliorating atrophy of hindlimb muscle after SCI. Meanwhile, the expression of neurotrophin-3 (NT-3) in the same spinal cord segment was significantly increased. These findings suggest that TANES and EA can augment the expression of NT-3 in the lumbar spinal cord that appears to protect the motor neurons as well as alleviate muscle atrophy.

Severe spinal cord injury (SCI) causes loss of neural connectivity and permanent functional deficits. Re-establishment of new neuronal relay circuits after SCI is therefore of paramount importance. The present study tested our hypothesis if co-culture of neurotrophin-3 (NT-3) gene-modified Schwann cells (SCs, NT-3-SCs) and TrkC (NT-3 receptor) gene-modified neural stem cells (NSCs, TrkC-NSCs) in a gelatin sponge scaffold could construct a tissue engineering neural network for re-establishing an anatomical neuronal relay after rat spinal cord transection. Eight weeks after transplantation, the neural network created a favorable microenvironment for axonal regeneration and for survival and synaptogenesis of NSC-derived neurons. Biotin conjugates of cholera toxin B subunit (b-CTB, a transneuronal tracer) was injected into the crushed sciatic nerve to label spinal cord neurons. Remarkably, not only ascending and descending nerve fibers, but also propriospinal neurons, made contacts with b-CTB positive NSC-derived neurons. Moreover, b-CTB positive NSC-derived neurons extended their axons making contacts with the motor neurons located in areas caudal to the injury/graft site of spinal cord. Further study showed that NT-3/TrkC interactions activated the PI3K/AKT/mTOR pathway and PI3K/AKT/CREB pathway affecting synaptogenesis of NSC-derived neurons. Together, our findings suggest that NT-3-mediated TrkC signaling plays an essential role in constructing a tissue engineering neural network thus representing a promising avenue for effective exogenous neuronal relay-based treatment for SCI., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Study Design: Transplanted primates' neural stem cells (NSCs) tissue engineering complex into spinal cord injury (SCI) model rats, analyze and evaluate the long-term effects of repairing., Objectives: Primate NSCs were cultured in self-assembling peptide nanofiber scaffolds to repair SCI., Setting: Sun Yat-sen Memorial Hospital, Guangzhou, China., Methods: Primate NSCs were isolated and cultured in self-assembling peptide nanofiber scaffolds. T10 SCI model was established; the rats were randomly divided into four groups: NSC plus self-assembling peptide scaffold group; NSC group; self-assembling peptide scaffold group; and control group. Immunohistochemical staining and electronic microscope were used to investigate the growth and differentiation of transplanted NSCs. The motor function of the hind limbs of rats was evaluated (P<0.05 was considered as statistically significant)., Results: NSCs and NSCs cultured in self-assembling peptide nanofiber scaffolds could be induced to differentiation into neurons, glial cells and oligodendrocytes in vitro. The primate NSC culture was established in self-assembling peptide scaffolds. No significant difference was seen in the differentiation rate between primate NSCs cultured in self-assembling peptide nanofiber scaffolds and primate NSCs cultured in regular medium. The motor function of the hind limbs in the NSC plus self-assembling peptide scaffold group was significantly better than that of the other three groups. In addition, the NSCs of the NSC group mainly differentiated into astrocytes., Conclusion: Transplantation of primate NSCs cultured in self-assembling peptide scaffolds is efficient for repairing the injured spinal cord and for improving the motor function of spinal cord in rats., Sponsorship: The National Natural Science Foundation of China; Science and Technology Office of Guangdong Province.

Hemophilic arthropathy is the most common chronic complication in patients with hemophilia. The pathogenesis of hemophilic arthropathy involves the inflammatory processes associated with rheumatoid arthritis (RA). Determining the severity and/or progression of joint damage is crucial when evaluating the effect of treatment modalities. Identifying reliable biomarkers in the peripheral blood of patients with hemophilic arthropathy may be beneficial in clinical practice. Circulating soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin, and P-selectin levels are elevated in patients with RA. Our study investigated whether these soluble adhesion molecules can be used as biological indicators in the course of joint damage in patients with hemophilia A.Patients with hemophilia A (mild, moderate, and severe) were enrolled. The plasma levels of sVCAM-1, E-selectin, and P-selectin in patients with hemophilia A and control were measured using specific enzyme-linked immunosorbent assay kits. Joint damages were evaluated using Pettersson scores.No statistically significant differences were observed in E-selectin and P-selectin levels between patients and controls. The sVCAM-1 level was significantly higher in patients with hemophilia A than in controls. The differences remained significant in patients with severe hemophilia A but not in patients with mild or moderate hemophilia A. The degree of hemophilic arthropathy was evaluated using Pettersson scores, and a score higher than 5 indicated marked arthropathy. Patients with more than 1 joint with marked arthropathy showed significantly higher sVCAM-1 levels.sVCAM-1 levels in patients with hemophilia A are associated with the severity of hemophilic arthropathy., Competing Interests: The authors have no conflicts of interest to disclose.

Despite the promising improvements made recently on fluorescence probes for the detection of enzymes and reactive small molecules, two fundamental problems remain: weaker fluorescence of many dyes in aqueous buffers and strong nonspecific signals in samples containing high protein levels. In this paper, we introduce a novel fluorescent probe encapsulated in protein cavity (FPEPC) concept as demonstrated by SNAP-tag protein and three environment-sensitive fluorescence probes to overcome these two problems. The probes were constructed by following the current probe design for enzymes and reactive small molecules but with an additional benzylguanine moiety for selective SNAP-tag conjugation. The SNAP-tag conjugated probes achieved quantitative nitroreductase and hydrogen sulfide detection in blood plasma, whereas analyte concentrations were overestimated up to 700-fold when bare fluorescent probes were employed for detection. Furthermore, detection sensitivity was increased dramatically, as our probes displayed 390-fold fluorescence enhancement upon SNAP-tag conjugation, in stark contrast to the weak fluorescence of the free probes in aqueous solutions. Compared with the conventional approaches where fluorescent probes are encapsulated into polymers and nanoparticles, our simple and general approach successfully overcame many key issues such as dye leakage, long preparation steps, inconsistent dye-host ratios, difficulty in constructing in situ in a complex medium, and limited application to detect only small metabolites.

Extracellular matrix (ECM) expression is temporally and spatially regulated during the development of stem cells. We reported previously that fibronectin (FN) secreted by bone marrow mesenchymal stem cells (MSCs) was deposited on the surface of gelatin sponge (GS) soon after culture. In this study, we aimed to assess the function of accumulated FN on neuronal differentiating MSCs as induced by Schwann cells (SCs) in three dimensional transwell co-culture system. The expression pattern and amount of FN of differentiating MSCs was examined by immunofluorescence, Western blot and immunoelectron microscopy. The results showed that FN accumulated inside GS scaffold, although its mRNA expression in MSCs was progressively decreased during neural induction. MSC-derived neuron-like cells showed spindle-shaped cell body and long extending processes on FN-decorated scaffold surface. However, after blocking of FN function by application of monoclonal antibodies, neuron-like cells showed flattened cell body with short and thick neurites, together with decreased expression of integrin β1. In vivo transplantation study revealed that autocrine FN significantly facilitated endogenous nerve fiber regeneration in spinal cord transection model. Taken together, the present results showed that FN secreted by MSCs in the early stage accumulated on the GS scaffold and promoted the neurite elongation of neuronal differentiating MSCs as well as nerve fiber regeneration after spinal cord injury. This suggests that autocrine FN has a dynamic influence on MSCs in a three dimensional culture system and its potential application for treatment of traumatic spinal cord injury. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1902-1911, 2016., (© 2016 Wiley Periodicals, Inc.)