Biosynthetic Polymalic Acid as a Delivery Nanoplatform for Translational Cancer Medicine.

Poly(ß-L-malic acid) (PMLA) is a natural polyester produced by numerous microorganisms. Regarding its biosynthetic machinery, a nonribosomal peptide synthetase (NRPS) is proposed to direct polymerization of L-malic acid in vivo. Chemically versatile and biologically compatible, PMLA can be used as an ideal carrier for several molecules, including nucleotides, proteins, chemotherapeutic drugs, and imaging agents, and can deliver multimodal theranostics through biological barriers such as the blood-brain barrier. We focus on PMLA biosynthesis in microorganisms, summarize the physicochemical and physiochemical characteristics of PMLA as a naturally derived polymeric delivery platform at nanoscale, and highlight the attachment of functional groups to enhance cancer detection and treatment.

A retrospective analysis of transanal surgical management of 291 cases with rectal foreign bodies.

BACKGROUND: Rectal foreign bodies (RFB) are quite uncommon except in very busy hospitals. Because of their rarity, it is seldom that the treating physicians have a standard approach to the diagnosis, technique of extraction, and post-extraction evaluation. This can be further complicated by the rather extreme variability of size, shape, and texture of the foreign bodies, as well as the potential extent of trauma to the rectum or distal colon. AIM: The objectives of this study were to delineate the demographics, classification of cause, and injury patterns of RFB and to present the results of the transanal surgical management of a large series of RFB. METHODS: We retrospectively collected extensive data from the hospital medical records of the 291 patients who presented with RFB to the emergency department of Shenyang Proctological Hospital (Shenyang, China) from 2012 July to 2020 December. Specifically, demographics, origins and circumstance of the RFB, complications, injuries, anesthesia method, and the results of the transanal surgical management were recorded and analyzed. RESULTS: Of the 291 RFB cases, 225 (77.3%) were male and 66 (22.7%) were female, with a mean age of 53.8 ± 15.5 years (range, 1 ~ 88 years). The circumstances of the RFB were categorized as swallowed, 199 cases (68.4%); self-inserted, 87 (29.9%); and iatrogenic, 5 (1.7%). The proportion of males in the self-inserted RFB group was significantly greater than the swallowed RFB group (t = 31.114, p = 0.000). In the swallowed RFB group, the most common anorectal injuries and pathological changes were the following: penetration into the mucosa (75 cases, 37.7%), perianal or submucosal abscess (27 cases, 13.6%), and penetration into the anal canal (18 cases, 9.0%). In the self-inserted RFB group, 64 (73.6%) of the 87 cases had an intact rectum, whereas 8 (9.2%) had rectal mucosal ulcers and bleeding, and 7 (8%) had rectal lacerations. In the iatrogenic RFB group, 3 cases (60%) had rectal mucosal ulcers and bleeding, and 2 cases (40%) had inflammation of the rectal mucosa. Regarding extraction procedures, in the swallowed group, 187(187/199; 94%) patients underwent a transanal surgical procedure, and all were successful. In the self-inserted group, 82 patients underwent the transanal surgical procedure, and 74 (74/82; 90.2%) were successful whereas it was unsuccessful in the remaining 8 patients (8/82, 9.8%). Three (3/4, 75%) patients with iatrogenic RFB were resolved by the transanal surgical procedure. CONCLUSION: Men were markedly more likely than women to have swallowed RFBs and self-inserted RFBs. No serious damage to the rectum and anus was found in cases of swallowed RFB. Moreover, most surgical operations to remove foreign bodies via the anus were successful in this category of RFB. In contrast, rectal injury was more severe in patients with self-inserted RFB, such as rectal laceration, rectal mucosal ulcer, and bleeding. Moreover, the transanal removal operation in patients with self-inserted RFB had a failure rate of nearly 10%. Thick, long, hard foreign bodies did present a great challenge to the operator. Therefore, if necessary, patients with foreign bodies may need to be promptly referred for transabdominal removal.

Differentiation of COVID-19 from seasonal influenza: A multicenter comparative study.

As coronavirus disease 2019 (COVID-19) crashed into the influenza season, clinical characteristics of both infectious diseases were compared to make a difference. We reported 211 COVID-19 patients and 115 influenza patients as two separate cohorts at different locations. Demographic data, medical history, laboratory findings, and radiological characters were summarized and compared between two cohorts, as well as between patients at the intensive care unit (ICU) andnon-ICU within the COVID-19 cohort. For all 326 patients, the median age was 57.0 (interquartile range: 45.0-69.0) and 48.2% was male, while 43.9% had comorbidities that included hypertension, diabetes, bronchitis, and heart diseases. Patients had cough (75.5%), fever (69.3%), expectoration (41.1%), dyspnea (19.3%), chest pain (18.7%), and fatigue (16.0%), etc. Both viral infections caused substantial blood abnormality, whereas the COVID-19 cohort showed a lower frequency of leukocytosis, neutrophilia, or lymphocytopenia, but a higher chance of creatine kinase elevation. A total of 7.7% of all patients possessed no abnormal sign in chest computed tomography (CT) scans. For both infections, pulmonary lesions in radiological findings did not show any difference in their location or distribution. Nevertheless, compared to the influenza cohort, the COVID-19 cohort presented more diversity in CT features, where certain specific CT patterns showed significantly more frequency, including consolidation, crazy paving pattern, rounded opacities, air bronchogram, tree-in-bud sign, interlobular septal thickening, and bronchiolar wall thickening. Differentiable clinical manifestations and CT patterns may help diagnose COVID-19 from influenza and gain a better understanding of both contagious respiratory illnesses.

A phase I/II clinical trial on the efficacy and safety of NKT cells combined with gefitinib for advanced EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. METHODS: The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. DISCUSSION: Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. TRIAL REGISTRATION: This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

[Establishment of a mouse model of testicular Occludin gene knockout based on the CRE/LOXP system].

OBJECTIVE: To establish a testicular Occludin gene knockout model in mice and observe the phenotypic changes. METHODS: Occludin-floxed (genotype Floxp/-) mice were constructed based on the Cre/loxp system, which were cross-bred with AQP2-cre (genotype Cre/-) mice to derive Occludin knockout mice (Genotype Floxp/Floxp Cre/-). The genotype of the F1 knockout mice was identified by PCR and Southern blot technology. The expression of the Occludin protein in the knockout mice was determined by qPCR, Western blot and immunohistochemistry to verify the success of the modeling. Comparisons were made in the sperm count between the model and normal mice, followed by analysis of their fertility. RESULTS: The target mice of Occludin knockout were successfully constructed, which, compared with the normal controls, showed significantly down-regulated expression of the occludin protein, decreased sperm count and reduced fertility (P < 0.05). CONCLUSIONS: Occludin gene knockout mice were successfully constructed, and deletion of Occludin affects the reproductive function of the mice.

[SP1 identified as a transcription factor of miR-122-5p].

OBJECTIVE: To study the transcription factors of the spermatogenesis-related promoter mir-122-5p. METHODS: SP1 and GATA4 were predicted as the possible transcription factors of the mir-122-5p promoter by bioinformatics analysis, followed by construction of the double luciferase pGL3-mir-122-5p promoter vector, pcDNA3.1 (+) -SP1 expression vector and pcDNA3.1 (+) -GATA4 expression vector, respectively. The pcDNA-SP1+pGL3-basic mixture plasmid and pcDNA-SP1+ pGL3-miR-122-5p promoter mixture plasmid, pcDNA-GATA4+pGL3-basic mixture plasmid and pcDNA-GATA4+pGL3-miR-122-5p promoter mixture plasmid were transferred into 293T cells. The enzyme activity was detected the Dual-Luciferase Reporter Assay System. RESULTS: The fluorescence value of the pcDNA3.1+pGL3-miR-122 promoter was 0.0362 ± 0.0004, significantly higher than that of the pcDNA3.1+pGL3-basic group (P < 0.05), indicating the successful construction of the mouse miR-122-5p promoter luciferase reporter plasmid. The fluorescence value was markedly higher in the pcDNA -SP1 + pGL3-miR-122-5p promoter than in the pcDNA -SP1+pGL3-basic group, suggesting that the transcription factor SP1 could promote the transcription of miR-122. There was no statistically significant difference in the fluorescence value between the pcDNA -gata4+pGL3-basic transfection and pcDNA -GATA4+pGL3-miR-122-5p promoter transfection groups, indicative of the inability of GATA4 to promote the transcription of miR-122-5p. CONCLUSIONS: The transcription factor SP1, rather than GATA4, can promote the transcription of miR-122-5p.

[Construction of RNA interfering lentiviral vector of occludin and its role in tight junctions].

OBJECTIVE: To investigate the role of occludin in tight junction (TJ) in vitro. METHODS: We constructed RNA interfering lentiviral vectors and transfected them into TM4 cells. Then we detected their inhibitory effect on occuldin by RT-PCR and Western blot and analyzed the role of occuldin in TJ using an in vitro TJ cell model. RESULTS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed. The results of RT-PCR and Western blot showed that pLenti 6.3-EGFP-occludin-miR-3 significantly inhibited the expression of occludin (P < 0.05), which was remarkably lower than in the blank control and the pLenti 6.3- EGFP transfection group (0.7534 ± 0.089 vs 1.000 and 1.056 ± 0.025, P < 0.05). The expression of occludin was markedly suppressed and the tightness of tight junctions decreased in the TM4 cells transfected with pLenti 6.3-EGFP-occludin-miR-3. CONCLUSIONS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed, and occludin is one of the functional proteins that maintain tight junctions.

Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay.

TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Here, we identified two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] from a patient with severe anemia, lactic acidosis, and developmental delay. Patient-derived immortalized lymphocytes showed decreased TOM70 expression, oligomerized TOM70 complex, and TOM 20/22/40 complex compared with expression in control lymphocytes. Functional analysis revealed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects, with complex IV being primarily affected. As a result, patient-derived cells grew slower in galactose medium and generated less ATP and more extracellular lactic acid than did control cells. In vitro cell model compensatory experiments confirmed the pathogenicity of TOMM70 variants since only wild-type TOM70, but not mutant TOM70, could restore the complex IV defect and TOM70 expression in TOM70 knockdown U2OS cells. Altogether, we report the first case of mitochondrial disease-causing mutations in TOMM70 and demonstrate that TOM70 is essential for multi-OXPHOS assembly. Mutational screening of TOMM70 should be employed to identify mitochondrial disease-causing gene mutations in the future.

Effects of Length and Loop Composition on Structural Diversity and Similarity of (G3TG3NmG3TG3) G-Quadruplexes.

A G-rich sequence containing three loops to connect four G-tracts with each ≥2 guanines can possibly form G-quadruplex structures. Given that all G-quadruplex structures comprise the stacking of G-quartets, the loop sequence plays a major role on their folding topology and thermal stability. Here circular dichroism, NMR, and PAGE are used to study the effect of loop length and base composition in the middle loop, and a single base difference in loop 1 and 3 on G-quadruplex formation of (G3HG3NmG3HG3) sequences with and without flanking nucleotides, where H is T, A, or C and N is T, A, C, or G. In addition, melting curve for G-quadruplex unfolding was used to provide relatively thermal stability of G-quadruplex structure after the addition of K+ overnight. We further studied the effects of K+ concentration on their stability and found structural changes in several sequences. Such (G3HG3NmG3HG3) configuration can be found in a number of native DNA sequences. The study of structural diversity and similarity from these sequences may allow us to establish the correlation between model sequences and native sequences. Moreover, several sequences upon interaction with a G-quadruplex ligand, BMVC, show similar spectral change, implying that structural similarity is crucial for drug development.

[Deletion of extracellular loops of occludin affects the tight junction of TM4 cells in mice].

OBJECTIVE: To analyze the functions of the two extracellular loops of occludin in the tight junction of TM4 cells in mice. METHODS: Using genetic engineering, we separately or simultaneously deleted two extracellular loops of occludin, cloned the three occludin genes without extracellular loops into the pcDNA3.1 expression vector, and transfected them into TM4 cells. Then we determined the expression of occludin by RT-PCR and Western blot, and analyze the effects of the extracellular loops of occludin on the tight junction of the TM4 cells with the in vitro cell line model. RESULTS: The results of sequencing showed that the expression vector of pcDNA3.1 - occludin Δ OCC1, pcDNA3.1 - occludin Δ OCC2 and pcDNA3.1 - occludin Δ OCC1 + OCC2 was constructed successfully. The mRNA and protein expressions of occludin in the non-extracellular loop groups were significantly higher than in the control group. Both the extracellular loops of occludin increased the tight junction of the TM4 cells. The macromolecular permeability in the TM4 cells was significantly lower in the pcDNA3.1 - occludin Δ OCC1 than in the pcDNA3.1 - occludin Δ OCC2 group (P < 0.05), indicating a higher impact of the second than the first extracellular loop on the tight junction of the TM4 cells. CONCLUSIONS: Both of the two extracellular loops of occludin can affect the tight junction of TM4 cells, the second even more significantly than the first one.

Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats.

Peripheral nerve injury results in limited nerve regeneration and severe functional impairment. Mesenchymal stem cells (MSCs) are a remarkable tool for peripheral nerve regeneration. The involvement of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) in peripheral nerve regeneration, however, remains unknown. In this study, we evaluated functional recovery and nerve regeneration in rats that received hUCMSC-EV treatment after nerve transection. We observed that hUCMSC-EV treatment promoted the recovery of motor function and the regeneration of axons; increased the sciatic functional index; resulted in the generation of numerous axons and of several Schwann cells that surrounded individual axons; and attenuated the atrophy of the gastrocnemius muscle. hUCMSC-EVs aggregated to rat nerve defects, down-regulated interleukin (IL)-6 and IL-1ß, up-regulated IL-10 and modulated inflammation in the injured nerve. These effects likely contributed to the promotion of nerve regeneration. Our findings indicate that hUCMSC-EVs can improve functional recovery and nerve regeneration by providing a favourable microenvironment for nerve regeneration. Thus, hUCMSC-EVs have considerable potential for application in the treatment of peripheral nerve injury.

Long Non-coding RNA XIST May Influence Cervical Ossification of the Posterior Longitudinal Ligament Through Regulation of miR-17-5P/AHNAK/BMP2 Signaling Pathway.

Long non-coding RNAs (lncRNAs) play an important role in the development of bone-related diseases. This study was conducted to investigate the role and mechanism of lncRNA X inactive specific transcript (XIST) in the occurrence of cervical ossification of the posterior longitudinal ligament (OPLL). Here, primary human ligament fibroblasts cells (LFCs) were isolated from 30 cases of OPLL and 30 normal cervical posterior longitudinal ligament (non-OPLL) tissues to perform the qPCR and Western blot assay. We found that the mRNA level of lncRNA XIST was significantly increased in OPLL LFCs compared to non-OPLL LFCs. By bioinformatics analysis, we found that lncRNA XIST has four binding sites for miR-17-5p and found that the mRNA level of miR-17-5p was also significantly decreased in OPLL LFCs compared to non-OPLL LFCs. Since AHNAK is the target gene of miR-17-5p, we further found that the expression of AHNAK was significantly reduced in non-OPLL LFCs after being transfected with miR-17-5p mimic. The qPCR results showed that the mRNA expressions of BMP2 and Runx2 were significantly decreased. After being transfected with lncRNA XIST siRNA in the non-OPLL LFCs, the mRNA levels of lncRNA XIST, AHNAK, BMP2, and Runx2 were significantly decreased and the phosphorylated protein of Smad1/5/8 was reduced. After being cultured by mechanical vibration, the mRNA levels of lncRNA XIST, AHNAK, BMP2, Runx2, COL1, OC, OPN, and Phospho1 were significantly increased, but the mRNA expression of miR-17-5p was significantly decreased. The expression of phosphorylated Smad1/5/8 protein was also significantly increased. Together, this study was the first to determine that XIST gene inhibition plays an important role in the occurrence of cervical OPLL, through the mechanism of regulation of miR-17-5P/AHNAK/BMP2 signaling pathway. Thus, XIST may be a potential target that could be modulated for the treatment of cervical OPLL.

Correlation Analysis of miR-122-5p and Occludin with Sperm Density in Oligospermia Patients' Sperm.

BACKGROUND: To analyze the correlation of miR-122-5p and occludin with sperm density in oligospermia patients' sperm. METHODS: The expression of miR-122-5p and its target protein occludin in the sperm and exfoliated cells of semen were studied using real-time reverse transcription-polymerase chain reaction and Western blot analysis. RESULTS: The expression level of miR-122-5p in the sperm and exfoliated cells of patients with oligospermia semen was 0.0880 ± 0.02581 and 0.5110 ± 0.1087, respectively, which were lower than those in the normal sperm (0.7840 ± 0.2318 and 7.000 ± 2.136), and the differences were significant. The expression of occludin in the sperm of patients with oligospermia was 3.725 ± 0.5870, which was significantly higher than that in the normal group (1.055 ± 0.03344). No difference was found in the expression of occludin between sperm and exfoliated cells of patients with oligospermia. The sperm density positively correlated with the expression of miR-122-5p in the sperm and exfoliated cells and negatively correlated with the expression of occludin in the sperm. CONCLUSIONS: The results of the study suggested that the low expression of miR-122-5p might affect the proliferation and differentiation of spermatogenic cells, leading to a decrease in the sperm count. The high expression of occludin also affected the tight junction of spermatogenic cells through testis and led to a decrease in the sperm count.

Endoplasmic reticulum stress regulates mechanical stress-induced ossification of posterior longitudinal ligament.

PURPOSE: The pathogenesis of ossification of posterior longitudinal ligament (OPLL) is not completely clear. Previous study has confirmed a single-pass type I endoplasmic reticulum (ER) membrane protein kinase (PERK), which is a major transducer of the ER stress, participates in the process of OPLL in vitro. This study aimed to demonstrate the role of ER stress in mechanical stress (MS)-induced OPLL. METHODS: The posterior longitudinal ligaments were collected intraoperatively. The expression of ER stress markers in ligament tissue samples was compared between OPLL and non-OPLL patients in vivo. Ligament fibroblasts were isolated and cultured. Loaded by MS, the expression of ER stress markers in fibroblasts deriving from non-ossified areas of the ligament tissues from OPLL patients was detected. The influence of inhibition of ER stress on MS-induced OPLL and activation of mitogen-activated protein kinase (MAPK) pathways by MS was also investigated. RESULTS: We confirmed the ER stress markers were highly expressed in non-ossified areas of the ligament tissues from OPLL patients but could barely be detected in the ligaments from non-OPLL patients in vivo. We also found ER stress could be activated by MS during the process of OPLL in vitro. Moreover, inhibition of ER stress could hinder MS-induced OPLL and activation of MAPK signaling pathways by MS in vitro. CONCLUSION: Activated ER stress was observed in OPLL patients both in vitro and in vivo. Mechanical stress could activate ER stress response in posterior longitudinal ligament fibroblasts and further promote OPLL in vitro. In this process, ER stress might work through the MAPK signaling pathways. These slides can be retrieved under Electronic Supplementary Material.

Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells.

BACKGROUND/AIMS: Mechanical stimulation and WNT signalling have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding the regulation of WNT signalling molecule expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. METHODS: Microarrays of BMSCs from elderly individuals or patients with osteoporosis (GSE35959) from the GEO database were analysed using GeneSight-Lite 4.1.6 (BioDiscovery) and C2 curated gene sets downloaded from Molecular Signatures Database (MSigDB). Realtime PCR and western blotting were used to measure the expression of the indicated genes. ALP and Alizarin red staining were used to evaluate the osteogenesis of BMSCs. RESULTS: In this study, we investigated whether mechanical loading directly regulates the expression of WNT signalling molecules and examined the role of WNT signalling in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found downregulation of the GPCR ligand binding gene set in the BMSCs of patients with osteoporosis. Then, we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. FZD4 was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, and the JNK signalling pathway was activated. FZD4 knockdown inhibited the mechanical stimuli-induced osteogenesis and JNK activity. More importantly, we found an activating effect of WNT5A and FZD4 that regulated bone formation in response to hindlimb unloading in mice, and pretreatment with WNT5A or activation of the expression of FZD4 partly rescued the osteoporosis caused by mechanical unloading. CONCLUSIONS: Our results demonstrate, for the first time, that mechanical stimulation alters the expression of genes involved in the osteogenic differentiation of BMSCs via the direct regulation of FZD4 and that therapeutic WNT5A and FZD saRNA may be an efficient strategy for enhancing bone formation under mechanical stimulation.

Inhibition of cytokine response to TLR stimulation and alleviation of collagen-induced arthritis in mice by Schistosoma japonicum peptide SJMHE1.

Helminth-derived products have recently been shown to prevent the development of inflammatory diseases in mouse models. However, most identified immunomodulators from helminthes are mixtures or macromolecules with potentially immunogenic side effects. We previously identified an immunomodulatory peptide called SJMHE1 from the HSP60 protein of Schistosoma japonicum. In this study, we assessed the ability of SJMHE1 to affect murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated by toll-like receptor (TLR) ligands in vitro and its treatment effect on mice with collagen-induced arthritis (CIA). We show that SJMHE1 not only modulates the cytokine production of murine macrophage (MΦ) and dendritic cell but also affects cytokine production upon coculturing with allogeneic CD4+ T cell. SJMHE1 potently inhibits the cytokine response to TLR ligands lipopolysaccharide (LPS), CpG oligodeoxynucleotides (CpG) or resiquimod (R848) from mouse splenocytes, and human PBMCs stimulated by LPS. Furthermore, SJMHE1 suppressed clinical signs of CIA in mice and blocked joint erosion progression. This effect was mediated by downregulation of key cytokines involved in the pathogenesis of CIA, such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-17, and IL-22 and up-regulation of the inhibitory cytokine IL-10, Tgf-ß1 mRNA, and CD4+ CD25+ Foxp3+ Tregs. This study provides new evidence that the peptide from S. japonicum, which is the 'safe' selective generation of small molecule peptide that has evolved during host-parasite interactions, is of great value in the search for novel anti-inflammatory agents and therapeutic targets for autoimmune diseases.

16 Gb/s PAM4 UWOC system based on 488-nm LD with light injection and optoelectronic feedback techniques.

A 16 Gb/s four-level pulse amplitude modulation (PAM4) underwater wireless optical communication (UWOC) system based on 488-nm laser diode (LD) with light injection and optoelectronic feedback techniques is proposed and successfully demonstrated. Experimental results show that such a 1.8-GHz 488-nm blue light LD with light injection and optoelectronic feedback techniques is enough forceful for a 16 Gb/s PAM4 signal underwater link. To the authors' knowledge, this study is the first to successfully adopt a 488-nm LD transmitter with light injection and optoelectronic feedback techniques in a PAM4 UWOC system. By adopting a 488-nm LD transmitter with light injection and optoelectronic feedback techniques, good bit error rate performance (offline processed by Matlab) and clear eye diagrams (measured in real-time) are achieved over a 10-m underwater link. The proposed system has the potential to play a vital role in the future UWOC infrastructure by effectively providing high transmission rate (16 Gb/s) and long underwater transmission distance (10 m).

Ossification of the posterior ligament is mediated by osterix via inhibition of the ß-catenin signaling pathway.

Ossification of the posterior longitudinal ligament (OPLL) involves ectopic calcification of the spinal ligament preferentially at the cervical spine. OPLL is associated with different diseases and occurs by endochondral ossification, which is associated with the activity of different transcription factors. However, the pathogenesis of OPLL remains unclear. Here, we investigated the role of osterix (Osx), a transcription factor that functions downstream of Runx2 and is an important regulator of osteogenesis, in the process of OPLL in a dexamethasone (Dex)-induced model of spinal ligament ossification. Our results showed that Osx is upregulated in patients with OPLL and during the ossification of ligament cells in parallel with the upregulation of osteogenic markers including osteocalcin (OCN), alkaline phosphatase (ALP) and collagen-1 (Col-1). Dex-induced ossification of ligament cells was associated with the downregulation and inactivation of ß-catenin, and these effects were offset by Osx knockdown. Activation of ß-catenin signaling abolished the effect of Dex on ossification and the upregulation of osteogenic markers. Taken together, our results suggest that OPLL is mediated by Osx via a mechanism involving the Wnt/ß-catenin signaling pathway, providing a basis for further research to identify potential targets for the treatment of OPLL.

Expansive open-door laminoplasty versus laminectomy and instrumented fusion for cases with cervical ossification of the posterior longitudinal ligament and straight lordosis.

PURPOSE: To identify whether expansive open-door laminoplasty (Lam) is more appropriate than laminectomy and instrumented fusion (LIF) for cases with ossification of the posterior longitudinal ligament (OPLL) and straight cervical lordosis. METHODS: A total of 67 cases were included and divided into Group Lam (n = 32) and Group LIF (n = 35), and the mean follow-up periods were 38 and 42 months, respectively. The cervical lordosis was elevated by C2-7 Cobb angle and cervical sagittal balance by C2-C7 sagittal vertical axis (SVA). Japanese Orthopedic Association (JOA), neurological recovery rate (RR) being calculated by the JOA, visual analog scale (VAS) and neck disability index (NDI) were used to assess clinical outcomes. RESULTS: Differences in general data between two groups were not significant. Total blood loss and operation duration in Group Lam were both significantly less than that in the Group LIF. By the final follow-up, the cervical lordosis significantly decreased in Group Lam and increased in Group LIF, the SVA significantly increased in Group Lam and kept unchanged in Group LIF, and the JOA, VAS, NDI significantly improved in both groups. Although there was no significant difference in RR between the two groups, cases in Group Lam had significantly larger incidence of postoperative kyphosis and kyphotic change rate, and less VAS, NDI and incidence of axial pain than cases in Group LIF. CONCLUSIONS: When compared with the LIF, the Lam is recommended for cases with OPLL and straight cervical lordosis when taking comparable neurological recovery, less axial pain and better neck function improvement into consideration.

The application of a new type of titanium mesh cage in hybrid anterior decompression and fusion technique for the treatment of continuously three-level cervical spondylotic myelopathy.

PURPOSE: To evaluate the efficacy and safety of a new type of titanium mesh cage (NTMC) in hybrid anterior decompression and fusion method (HDF) in treating continuously three-level cervical spondylotic myelopathy (TCSM). METHODS: Ninety-four cases who had TCSM and accepted the HDF from Jan 2007 to Jan 2010 were included. Clinical and radiological outcomes were compared between cases who had the NTMC (Group A, n = 45) and traditional titanium mesh cage (TTMC, Group B, n = 49) after corpectomies. Each case accepted one polyetheretherketone cage (PEEK) after discectomy. RESULTS: Mean follow-up were 74.4 and 77.3 months in Group A and B, respectively (p > 0.05). Differences in cervical lordosis (CL), segmental lordosis (SL), anterior segmental height (ASH) and posterior segmental height (PSH) between two groups were not significant preoperatively, 3-days postoperatively or at final visit. However, losses of the CL, SL, ASH and PSH were all significantly larger in Group B at the final visit, so did incidences of segmental subsidence and severe subsidence. Difference in preoperative Japanese Orthopedic Association (JOA), visual analog scale (VAS), neck disability index (NDI) or SF-36 between two groups was not significant. At the final visit, fusion rate, JOA, and SF-36 were all comparable between two groups, but the VAS and NDI were both significantly greater in Group B. CONCLUSIONS: For cases with TCSM, HDF with the NTMC and TTMC can provide comparable radiological and clinical improvements. But application of the NTMC in HDF is of advantages in decreasing the subsidence incidence, losses of lordosis correction, VAS and NDI.