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Background The Wisteria floribunda agglutinin-positive human Mac-2-binding protein ( WFA+-M2 BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA+-M2 BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. Aim To evaluate the diagnostic ability of WFA+-M2 BP for liver fibrosis in the clinical setting and the clinical utility of WFA+-M2 BP for predicting the efficacy of direct-acting anti-viral ( DAA) treatment for chronic hepatitis C patients. Methods The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA+-M2 BP and treatment efficacy was evaluated. Results The serum WFA+-M2 BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index ( COI) for WFA+-M2 BP for diagnosing advanced fibrosis. The sustained virological response ( SVR) rate was significantly, negatively correlated with the serum WFA+-M2 BP level. Multiple logistic regression analysis found a low serum WFA+-M2 BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA+-M2 BP level. Conclusion Serum WFA+-M2 BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective observational study., Objectives: To evaluate the long-term recurrence rates and functional status of patients with thoracic ossification of the posterior longitudinal ligament (OPLL) after decompression and posterior fusion surgery., Methods: Thirty-seven consecutive patients who underwent posterior thoracic spine surgery at a single institution were retrospectively reviewed. The long-term neurological and functional outcomes of 25 patients who were followed up for ≥10 years after surgery were assessed. Factors associated with the recurrence of myelopathy were also analyzed., Results: The mean preoperative Japanese Orthopaedic Association score was 3.7, which improved to 6.5 at postoperative year 2 and declined to 6.0 at a mean follow-up of 18 years. No patient experienced a relapse of myelopathy due to OPLL within the instrumented spinal segments. However, 15 (60%) patients experienced late neurological deterioration, 10 of whom had a relapse of myelopathy due to OPLL or ossification of the ligamentum flavum (OLF) in the region outside the primary operative lesion, while 4 developed myelopathy due to traumatic vertebral fracture of the ankylosed spine. Young age, a high body mass index, and lumbar OPLL are likely associated with late neurological deterioration., Conclusions: Decompression and posterior instrumented fusion surgery is a reliable surgical procedure with stable long-term clinical outcomes for thoracic OPLL. However, as OPLL may progress through the spine, attention should be paid to the recurrence of paralysis due to OPLL or OLF in regions other than the primary operative lesion and vertebral fractures of the ankylosed spine after surgery for thoracic OPLL., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We report the complete sequence of Selenomonas species strain TAMA-11512, isolated from the blood culture of a septic patient. The phylogeny and average nucleotide identity show that the strain TAMA-11512 is considered a novel bacterial species in Selenomonas genus., Competing Interests: The authors declare no conflict of interest.

Objective: Although type II collagen could have marked potential for developing cartilage tissue engineering (CTE) scaffolds, its erratic supply and viscous nature have limited these studies, and there are no studies on the use of marine-derived type II collagen fibrils for CTE scaffold materials. In this study, we aimed to generate a fibril-based, thin-layered scaffold from marine-derived type II collagen and investigate its chondrogenic potential., Methods: Time-lapse observations revealed the cell adhesion process. The Cell Counting Kit-8 (CCK-8) assay, light microscopy, and scanning electron microscopy were performed to detect proliferation and filopodium morphology. Alcian blue staining was used to show the deposition of extracellular secretions, and qRT-PCR was performed to reveal the expression levels of chondrogenesis-related genes., Results: The cell adhesion speed was similar in both fibril-coated and control molecule-coated groups, but the cellular morphology, proliferation, and chondrogenesis activity differed. On fibrils, more elongated finer filopodia showed inter-cell communications, whereas the slower proliferation suggested an altered cell cycle. Extracellular secretions occurred before day 14 and continued until day 28 on fibrils, and on fibrils, the expression of the chondrogenesis-related genes Sox9 ( p ​< ​0.001 ), Col10a1 ( p ​< ​0.001 ), Acan ( p ​< ​0.001 ), and Col2a1 ( p  ​= ​0.0049) was significantly upregulated on day 21., Conclusion: Marine-derived type II collagen was, for the first time, fabricated into a fibril state. It showed rapid cellular affinity and induced chondrogenesis with extracellular secretions. We presented a new model for studying chondrogenesis in vitro and a potential alternative material for cell-laden CTE research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2024 The Authors.)

Adolescent idiopathic scoliosis (AIS), the most common pediatric musculoskeletal disorder, causes a three-dimensional spine deformity. Lenke type 5 AIS is defined as a structural thoracolumbar/lumbar curve with nonstructural thoracic curves. Although a rod curvature will affect clinical outcomes, intraoperative contouring of the straight rod depends on the surgeon's knowledge and experience. This study aimed to determine the optimum rod geometries to provide a pre-bent rod system for posterior spinal surgery in patients with Lenke type 5 AIS. These pre-bent rods will be beneficial for achieving proper postoperative outcomes without rod contouring based on surgeon experience. We investigated 20 rod geometries traced in posterior spinal reconstruction in patients with Lenke type 5 AIS. The differences between the center point clouds in each cluster were evaluated using the iterative closest point (ICP) method with modification. Before the evaluation using the ICP method, the point clouds were divided into four clusters based on the rod length using a hierarchical cluster analysis. Because the differences in the values derived from the ICP method were <5 mm for each length-based cluster, four representative rod shapes were generated from the length-based clusters. We identified four optimized rod shapes that will reduce operation time, leading to a decreased patient and surgeon burden.

Alzheimer's disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (Aβ), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with Aβ. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits Aβ aggregation, as well as neurotoxicity and immunoreactivity in Aβ-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited Aβ oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMFβ). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMFβ in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against Aβ pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding., (© 2023. The Author(s).)

Background and Objectives: Although full endoscopic lumbar discectomy with the transforaminal approach (FED-TF) is a minimally invasive spinal surgery for lumbar disc herniation, the lumbosacral levels present anatomical challenges when performing FED-TF surgery due to the presence of the iliac bone. Materials and Methods: In this study, we simulated whether FED-TF surgery could be safely performed on a total of 52 consecutive cases with L5-S1 or L5-L6 disc herniation using fused three-dimensional (3D) images of the lumbar nerve root on magnetic resonance imaging (MRI) created with artificial intelligence and of the lumbosacral spine and iliac on computed tomography (CT) images. Results: Thirteen of the fifty-two cases were deemed operable according to simulated FED-TF surgery without foraminoplasty using the 3D MRI/CT fusion images. All 13 cases underwent FED-TF surgery without neurological complications, and their clinical symptoms significantly improved. Conclusions: Three-dimensional simulation may allow for the assessment from multiple angles of the endoscope entry and path, as well as the insertion angle. FED-TF surgery simulation using 3D MRI/CT fusion images could be useful in determining the indications for full endoscopic surgery for lumbosacral disc herniation.

This study aimed to evaluate the lowest instrumented vertebra translation (LIV-T) in the surgical treatment of thoracolumbar/lumbar adolescent idiopathic scoliosis and to analyze the radiographic parameters in relation to LIV-T and L4 tilt and global coronal balance. A total of 62 patients underwent posterior spinal fusion (PSF, n = 32) or anterior spinal fusion (ASF, n = 30) and were followed up for a minimum of 2 years. The mean preoperative LIV-T was significantly larger in the ASF group than the PSF ( p < 0.01), while the final LIV-T was equivalent. LIV-T at the final follow-up was significantly correlated with L4 tilt and the global coronal balance (r = 0.69, p < 0.01, r = 0.38, p < 0.01, respectively). Receiver-operating characteristic analysis for good outcomes, with L4 tilt <8° and coronal balance <15 mm at the final follow-up, calculated the cutoff value of the final LIV-T as 12 mm. The cutoff value of preoperative LIV-T that would result in the LIV-T of ≤12 mm at the final follow-up was 32 mm in PSF, although no significant cutoff value was calculated in ASF. ASF can centralize the LIV better than PSF with a shorter segment fusion, and could be useful in obtaining a good curve correction and global balance without fixation to L4 in cases with large preoperative LIV-T., Competing Interests: The authors declare no conflict of interest.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue repair and reduces discogenic pain, and a combination of ultra-purified, Good Manufacturing Practice (GMP)-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs), and the UPAL gel increasingly enhanced IVD regeneration in animal models. This study investigated the therapeutic efficacy of injecting a mixture of REC and UPAL non-gelling solution for discogenic pain and IVD regeneration in a rat caudal nucleus pulposus punch model. REC and UPAL mixture and UPAL alone suppressed not only the expression of TNF-α, IL-6, and TrkA ( p < 0.01, respectively), but also IVD degeneration and nociceptive behavior compared to punching alone ( p < 0.01, respectively). Furthermore, REC and UPAL mixture suppressed these expression levels and nociceptive behavior compared to UPAL alone ( p < 0.01, respectively). These results suggest that this minimally invasive treatment strategy with a single injection may be applied to treat discogenic pain and as a regenerative therapy.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Early detection of deformity and timely intervention, such as brace treatment, can help inhibit progressive changes. A three-dimensional (3D) depth-sensor imaging system with a convolutional neural network was previously developed to predict the Cobb angle. The purpose of the present study was to (1) evaluate the performance of the deep learning algorithm (DLA) in predicting the Cobb angle and (2) assess the predictive ability depending on the presence or absence of clothing in a prospective analysis. We included 100 subjects with suspected AIS. The correlation coefficient between the actual and predicted Cobb angles was 0.87, and the mean absolute error and root mean square error were 4.7° and 6.0°, respectively, for Adam's forward bending without underwear. There were no significant differences in the correlation coefficients between the groups with and without underwear in the forward-bending posture. The performance of the DLA with a 3D depth sensor was validated using an independent external validation dataset. Because the psychological burden of children and adolescents on naked body imaging is an unignorable problem, scoliosis examination with underwear is a valuable alternative in clinics or schools.

We investigated the pharmacokinetics of alogliptin (AG) at the cell and tissue level in healthy Wistar rats and a type 2 diabetic Goto-Kakizaki (GK) rat model. Immunohistochemistry of the renal tissue in these rats, post 1 hr of AG administration, showed that the signal was observed in the glomeruli, proximal tubule S3 segments, distal tubules, collecting ducts, and only in the brush border of the epithelial cells of the proximal tubule S1, S2 segments. After 6 hr of AG administration, the staining intensity of the regions other than the S3 segments was considerably reduced in Wistar rats, with no change observed in GK rats. At 24 hr, the staining intensity was considerably reduced, even in GK rats; however, the staining of the S3 segment remained unaltered in both. Hepatocytes in zone III of the hepatic lobule were more intensely stained than those in zone I in Wistar rats at 1 hr. However, almost no staining was observed in the hepatocytes of GK rats at 1 hr. Complete loss of signal was observed in the hepatocytes of the Wistar rats after 6 hr. This study revealed that the pharmacokinetics of AG in GK rats are different from those in Wistar rats., Competing Interests: VThe authors declare no conflicts of interest., (2022 The Japan Society of Histochemistry and Cytochemistry.)

Cartilage is primarily composed of proteoglycans and collagen. Bioactive compounds derived from animal cartilage, such as chondroitin sulfate and type II collagen, have multiple bioactivities and are incorporated in popular health products. The aging population and increases in degenerative and chronic diseases will stimulate the rapid growth of market demand for cartilage products. Commercial production of bioactive compounds primarily involves the cartilages of mammals and poultry. However, these traditional sources are associated zoonosis concerns; thus, cartilage products from the by-products of fish processing has gained increasing attention because of their high level of safety and other activities. In this review, we summarize the current state of research into fish-derived cartilage products and their application, and discuss future trends and tasks to encourage further expansion and exploitation. At present, shark cartilage is the primary source of marine cartilage. However, the number of shark catches is decreasing worldwide, owing to overfishing. This review considers the potential alternative fish cartilage sources for industrialization. Three keys, the sustainable production of fish, new fish-processing model, and market demand, have been discussed for the future realization of efficient fish cartilage use. The industrialization of fish-derived cartilage products is beneficial for achieving sustainable development of local economies and society., Competing Interests: 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., (© 2022 Published by Elsevier B.V.)

Lumbar intervertebral disc (IVD) herniation causes severe low back pain (LBP), which results in substantial financial and emotional strains. Despite the effectiveness of discectomy, there is no existing treatment for post-operative LBP induced by progressive IVD degeneration. Two key factors of LBP are intradiscal inflammation, indicated by tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and sensory nerve ingrowth into the inner layer of the annulus fibrosus, triggered by nerve growth factor/high-affinity tyrosine kinase A (TrkA) signalling. In an animal models of discectomy, the bioresorbable ultra-purified alginate (UPAL) gel with an extremely low-toxicity has been effective in acellular tissue repair. We aimed to investigate whether UPAL gel can alleviate LBP using a rat nucleus pulposus (NP) punch model and a rabbit NP aspirate model. In both models, we assessed TNF-α and IL-6 production and TrkA expression within the IVD by immunohistochemistry. Further, histological analysis and behavioural nociception assay were conducted in the rat model. UPAL gel implantation suppressed TNF-α and IL-6 production, downregulated TrkA expression, inhibited IVD degeneration, and reduced nociceptive behaviour. Our results suggest the potential of UPAL gel implantation as an innovative treatment for IVD herniation by reducing LBP and preventing IVD degeneration after discectomy.

Ribonucleoside triphosphates are often incorporated into genomic DNA during DNA replication. The accumulation of unrepaired ribonucleotides is associated with genomic instability, which is mediated by DNA topoisomerase 1 (Top1) processing of embedded ribonucleotides. The cleavage initiated by Top1 at the site of a ribonucleotide leads to the formation of a Top1-DNA cleavage complex (Top1cc), occasionally resulting in a DNA double-strand break (DSB). In humans, tyrosyl-DNA phosphodiesterases (TDPs) are essential repair enzymes that resolve the trapped Top1cc followed by downstream repair factors. However, there is limited cellular evidence of the involvement of TDPs in the processing of incorporated ribonucleotides in mammals. We assessed the role of TDPs in mutagenesis induced by a single ribonucleotide embedded into DNA. A supF shuttle vector site-specifically containing a single riboguanosine (rG) was introduced into the human lymphoblastoid TK6 cell line and its TDP1-, TDP2-, and TDP1/TDP2-deficient derivatives. TDP1 and TDP2 insufficiency remarkably decreased the mutant frequency caused by an embedded rG. The ratio of large deletion mutations induced by rG was also substantially lower in TDP1/TDP2-deficient cells than wild-type cells. Furthermore, the disruption of TDPs reduced the length of rG-mediated large deletion mutations. The recovery ratio of the propagated plasmid was also increased in TDP1/TDP2-deficient cells after the transfection of the shuttle vector containing rG. The results suggest that TDPs-mediated ribonucleotide processing cascade leads to unfavorable consequences, whereas in the absence of these repair factors, a more error-free processing pathway might function to suppress the ribonucleotide-induced mutagenesis. Furthermore, base substitution mutations at sites outside the position of rG were detected in the supF gene via a TDPs-independent mechanism. Overall, we provide new insights into the mechanism of mutagenesis induced by an embedded ribonucleotide in mammalian cells, which may lead to the fatal phenotype in the ribonucleotide excision repair deficiency., Competing Interests: The authors have declared that no competing interests exist.

Eukaryotic transcription is epigenetically regulated by chromatin structure and post-translational modifications (PTMs). For example, lysine acetylation in histone H4 is correlated with activation of RNA polymerase I-, II- and III-driven transcription from chromatin templates, which requires prior chromatin remodeling. However, quantitative understanding of the contribution of particular PTM states to the sequential steps of eukaryotic transcription has been hampered partially because reconstitution of a chromatin template with designed PTMs is difficult. In this study, we reconstituted a di-nucleosome with site-specifically acetylated or unmodified histone H4, which contained two copies of the Xenopus somatic 5S rRNA gene with addition of a unique sequence detectable by hybridization-assisted fluorescence correlation spectroscopy. Using a Xenopus oocyte nuclear extract, we analyzed the time course of accumulation of nascent 5S rRNA-derived transcripts generated on chromatin templates in vitro. Our mathematically described kinetic model and fitting analysis revealed that tetra-acetylation of histone H4 at K5/K8/K12/K16 increases the rate of transcriptionally competent chromatin formation ∼3-fold in comparison with the absence of acetylation. We provide a kinetic model for quantitative evaluation of the contribution of epigenetic modifications to chromatin transcription., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)