Effects of PGE1 on the ERS pathway in neonatal rats with hyperoxic lung injury.

BACKGROUND: With the increase in the number of low birth weight infants, oxygen therapy is more widely used. However, chronic high-concentration oxygen environments lead to hyperoxic lung injury in children, which in turn leads to bronchopulmonary dysplasia (BPD). PGE1 is widely used in the clinic for its ability to inhibit inflammation and improve circulation. Therefore, we further investigated whether PGE-1 has a therapeutic effect on hyperoxic lung injury. METHODS: Hyperoxic lung injury model was adopted for investigating the interventional effects and underlying mechanisms of intraperitoneal injection of prostaglandin E1 (PGE-1) on hyperoxic lung injury in newborn rats via relevant experimental techniques, such as Diff-Quick staining, lung wet dry specific gravity measurements, HE staining, TUNEL staining, ELISA, and the Western blot method. RESULTS: Inflammatory and apoptotic cells in the PGE1-treated group were significantly lower than those in the hyperoxic lung injury group (p < 0.05); and the contents of IL-1ß, IL-6 and TNF-α in the treated group were significantly lower than those in the model group (p < 0.05). Caspase-3, CHOP, GRP78 and Bcl-2/Bax protein expression in the treatment group was significantly lower than that in the model group (p < 0.05). CONCLUSION: PGE-1 has a therapeutic effect on hyperoxic lung injury in neonatal rats. IMPACT: PGE1 treatment reduces levels of inflammatory cells and pro-inflammatory cytokines and decreases apoptosis. PGE1 has a therapeutic effect on BPD through the endoplasmic reticulum stress pathway. This study offers the possibility of PGE1 for the treatment of BPD.

How does the correction in lumbar lordosis affect the spinopelvic realignments in degenerative lumbar scoliosis underwent scoliosis surgery?

BACKGROUND: To evaluate the effects of correction in lumbar lordosis (LL) that have on full-body realignments in patients with degenerative lumbar scoliosis (DLS) who had undergone long sacroiliac fusion surgery. METHODS: A multi-center retrospective study including 88 DLS patients underwent the surgical procedure of long sacroiliac fusion with instrumentations was performed. Comparisons of radiographic and quality-of-life (QoL) data among that at the pre-operation, the 3rd month and the final follow-up were performed. The correlations between the LL correction and the changes in other spinopelvic parameters were explored using Pearson-correlation linear analysis and linear regression analysis. The correlation coefficient (r) and the adjusted r2 were calculated subsequently. RESULTS: All radiographic and QoL data improved significantly (P < 0.001) after the surgical treatments. The LL correction correlated (P < 0.001) with the changes in the sacral slope (SS, r = 0.698), pelvic tilt (PT, r = -0.635), sagittal vertical axis (SVA, r = -0.591), T1 pelvic angle (TPA, r = -0.782), and the mismatch of pelvic incidence minus lumbar lordosis (PI-LL, r = -0.936), respectively. Moreover, LL increased by 1° for each of the following spinopelvic parameter changes (P < 0.001): 2.62° for SS (r2 = 0.488), -4.01° for PT (r2 = 0.404), -4.86° for TPA (r2 = 0.612), -2.08° for the PI-LL (r2 = 0.876) and -15.74 mm for SVA (r2 = 0.349). Changes in the thoracic kyphosis (r = 0.259) and pelvic femur angle (r = 0.12) were independent of the LL correction, respectively. CONCLUSIONS: LL correction correlated significantly to the changes in spinopelvic parameters; however, those independent variables including the thoracic spine and hip variables probably be remodeled themselves to maintain the full-body balance in DLS patients underwent the correction surgery.

TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease.

Aggregation of tau into filamentous inclusions underlies Alzheimer's disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.

Clinical Outcomes After Arthroscopic Microfracture Treatment of Coexisting Talar and Tibial Osteochondral Lesions.

Background: Despite increased recognition of coexisting tibial and talar osteochondral lesions (OCLs), the risk factors influencing clinical outcomes remain unclear. Purpose: To report clinical follow-up results after arthroscopic microfracture surgery in patients with OCLs of the distal tibial plafond and talus and assess possible factors affecting these clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: A total of 40 patients with coexisting talar and tibial OCLs who underwent arthroscopic microfracture surgery were included. For analysis, the study used the American Orthopaedic Foot & Ankle Society (AOFAS) scale, Karlsson-Peterson scale, and visual analog scale (VAS) for pain for clinical evaluations on the day before surgery, 12 months after surgery, and at the last follow-up. A stepwise regression model and Spearman rank correlation were used to assess possible factors affecting these clinical outcomes. Results: The median follow-up time was 34.5 months (interquartile range [IQR], 26.5-54 months). At the final follow-up, the cohort included 40 patients (26 men and 14 women) with a mean age of 38.8 years (range, 19-60 years). The median AOFAS score increased from 57.5 (IQR, 47-65) before surgery to 88 (IQR, 83-92.5) at the final follow-up, the median Karlsson-Peterson score increased from 48 (IQR, 38.5-67) to 82 (IQR, 76-92), and the median VAS score improved from 5 (IQR, 4-6) to 1 (IQR, 0-2). All scale scores showed significant differences between the preoperative and final follow-up evaluations (P < .001). In the stepwise regression model and Spearman rank correlation analysis, the grade of tibial OCL had a significant independent effect on the final postoperative AOFAS scores of the patients (ß = -0.502, P = .001; r = -0.456, P = .003). The size of the tibial lesion also had a significant independent effect on the final postoperative Karlsson-Peterson scores of the patients (ß = -0.444, P = .004; r = -0.357, P = .024). Conclusion: Arthroscopic microfracture treatment for coexisting talar and tibial OCLs can achieve good short- to midterm clinical outcomes. The grade and size of tibial OCLs are the main risk factors affecting the prognostic functional scores of such patients.

The effects of Twinlight laser treatment on the titanium surface proliferation and osteogenic differentiation of mesenchymal stem cells.

BACKGROUND: The study aimed to observe the effects of a Twinlight laser on the titanium surface proliferation of inflammatory Mesenchymal stem cells (MSCs), inflammatory cytokine expression, and osteogenic differentiation. METHODS: The MSCs were collected from bone tissue of healthy individuals.The cellular inflammatory model was established with 1 µg/mL lipopolysaccharide (LPS).Under the cellular inflammatory model,divided into five groups: the normal control group (C); the inflammatory control group (L); Er:YAG laser group (L + E); Nd:YAG laser group (L + N); Er:YAG laser and Nd:YAG laser group (L + E + N). The treated cells were inoculated onto titanium disks.The normal and inflammatory MSCs on the surface of titanium surface were examined by CCK-8, scanning election microscopy (SEM), quantitative real-time polymerase chain reaction (qRT­PCR) and other methods for their proliferation, growth pattern, expression of inflammatory factors Interleukin-6 (IL-6), Interleukin-8 (IL-8) and osteogenic genes Runx2 (Runt-related transcription factor 2) and alkaline phosphatase (ALP), providing the theoretical basis and experimental data for the Twinlight laser-assisted treatment of peri-implantitis. Statistical analyses were performed using a Student's t test with SPSS 17.0 software. RESULTS: Through observation using SEM, the cell densities of the L + E + N, L + E, and L + N groups were similar, but cell bodies in the L + E + N group were fuller and each had more than two pseudopodia. The expression level of IL-6 mRNA in the L, L + N, L + E, and L + E + N groups was higher than in group C (P < 0.05), and the expression level of IL-8 mRNA in the L + E + N group was significantly lower than in group L (P < 0.0001). On day 7, the expression level of ALP mRNA in the L, L + N, L + E, and L + E + N groups was lower than in group C (P < 0.05). On day 14, there was no significant difference in the expression level of ALP mRNA among the L + N, L + E + N, and C groups (P > 0.05). On day 7, the expression level of RUNX2 mRNA in the L + E + N group was higher than in group L (P < 0.001). On day 14, the expression level of RUNX2 mRNA in the L + E + N group was higher than in group L (P < 0.01). CONCLUSION: Twinlight laser treatment promoted cell proliferation, inhibited the expression of inflammatory cytokines, and effectively enhanced the osteogenic differentiation of cells on a titanium surface.

The miR164a-NAM3 module confers cold tolerance by inducing ethylene production in tomato.

Because of a high sensitivity to cold, both the yield and quality of tomato (Solanum lycopersicum L.) are severely restricted by cold stress. The NAC transcription factor (TF) family has been characterized as an important player in plant growth, development, and the stress response, but the role of NAC TFs in cold stress and their interaction with other post-transcriptional regulators such as microRNAs in cold tolerance remains elusive. Here, we demonstrated that SlNAM3, the predicted target of Sl-miR164a/b-5p, improved cold tolerance as indicated by a higher maximum quantum efficiency of photosystem II (Fv/Fm), lower relative electrolyte leakage, and less wilting in SlNAM3-overexpression plants compared to wild-type. Further genetic and molecular confirmation revealed that Sl-miR164a/b-5p functioned upstream of SlNAM3 by inhibiting the expression of the latter, thus playing a negative role in cold tolerance. Interestingly, this role is partially mediated by an ethylene-dependent pathway because either Sl-miR164a/b-5p silencing or SlNAM3 overexpression improved cold tolerance in the transgenic lines by promoting ethylene production. Moreover, silencing of the ethylene synthesis genes, SlACS1A, SlACS1B, SlACO1, and SlACO4, resulted in a significant decrease in cold tolerance. Further experiments demonstrated that NAM3 activates SlACS1A, SlACS1B, SlACO1, and SlACO4 transcription by directly binding to their promoters. Taken together, the present study identified the miR164a-NAM3 module conferring cold tolerance in tomato plants via the direct regulation of SlACS1A, SlACS1B, SlACO1, and SlACO4 expression to induce ethylene synthesis.

Outcomes of Single-Stage Versus Staged Treatment of Osteochondral Lesions in Patients With Chronic Lateral Ankle Instability: A Prospective Randomized Study.

BACKGROUND: There is controversy about whether treatment of chronic lateral ankle instability (CLAI) with osteochondral lesions of the talus (OLT) can be performed concurrently. PURPOSE: To investigate the midterm results of arthroscopic treatment of CLAI combined with OLT in different surgical settings. It was hypothesized that the outcomes of treating both injuries at the same time would not be inferior to those of staged surgery. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Included were 103 patients with both CLAI and OLT who underwent arthroscopic microfracture surgery and an open, modified Broström-Gould procedure for ligament repair from January 2015 to December 2016. The patients were assigned randomly to a staged group (51 patients) and a single-stage group (52 patients). The staged group underwent arthroscopic debridement of the OLT and microfracture, then rehabilitation for 4 to 6 months before undergoing modified Broström-Gould ligament repair. The single-stage group underwent both procedures simultaneously. Clinical evaluations were performed on the day before surgery and at 12-month, 24-month, and final follow-up periods using the Karlsson-Peterson score, American Orthopaedic Foot & Ankle Society (AOFAS) score, and pain visual analog scale. The Karlsson-Peterson score at 24 months postoperatively was considered the primary outcome. The predefined noninferiority margin for the primary outcome was -5 points. RESULTS: At the final follow-up, 50 patients in the single-stage group and 48 patients in the staged group completed the study. The median lesion size was 0.72 cm2 (interquartile range [IQR], 0.5-1.12 cm2) in the single-stage group and 0.84 cm2 (IQR, 0.7-1.05 cm2) in the staged group. At 12-month follow-up, the single-stage group had a significantly higher median Karlsson-Peterson score (79 [IQR, 70-85] vs 75 [IQR 65-80] for staged; P = .024) and median AOFAS score (85 [IQR, 76-89] vs 79.5 [IQR, 70-87] for staged; P = .045). At 24-month follow-up, the median difference in the Karlsson-Peterson score for single-stage versus staged surgery was 2 points (95% CI, -2 to 5 points), and the confidence interval was greater than the predefined value. CONCLUSION: At midterm follow-up, there was no clinical difference between single-stage versus staged surgery to treat CLAI with OLT. Single-stage surgery achieved better clinical outcomes than staged surgery at short-term follow-up.

Effect of Twinlight Laser on the Attachment of Human Gingival Fibroblasts to the Root Surface In Vitro.

BACKGROUND This study aimed to compare the effectiveness of subgingival scaling and root planing with the Twinlight laser, Er: YAG laser, and hand instrumentation on the removal of endotoxin and attachment of human gingival fibroblasts (HGFs) to cementum surfaces in vitro. MATERIAL AND METHODS Single-rooted teeth extracted for periodontal disease were collected and divided into 3 groups: group A, root planing with Gracey curet no. 5/6; group B, irradiation with Er: YAG laser; group C, irradiation with Er: YAG laser and Nd: YAG laser. Endotoxins were determined by the limulus amebocyte lysate test. Cell attachment and proliferation of HGFs on root specimens were evaluated by cell counting kit-8 assay. The root surface and cell morphology were observed by scanning electron microscope. RESULTS A flat root surface with scratches was found in group A, Group B had a homogeneous rough morphology without carbonization, and group C had a non-homogeneous rough morphology with ablation. The endotoxin concentration was highest in group A (P<0.05) and lowest in group C (P>0.05). HGFs cultured in group B showed significantly increased adhesion and proliferation compared with groups A and C (P<0.05). HGFs in group B were well attached, covered densely by pseudopodia. HGFs in group A were round with poor extension and short pseudopodia, while the cells in the group C were in narrow, triangular, or polygonal shapes. CONCLUSIONS Twinlight laser-assisted periodontal treatment effectively improved the biocompatibility of root surface and promoted the attachment and proliferation of fibroblasts by removing calculus and reducing the concentration of endotoxins.

Computational Alanine Scanning Reveals Common Features of TCR/pMHC Recognition in HLA-DQ8-Associated Celiac Disease.

In HLA-DQ8-associated celiac disease, Gliadin-γ1 or Gliadin-α1 peptide is presented to the cell surface and recognized by several types of T-cell receptor (TCR), but it is still unclear how the TCR, peptide, and the major histocompatibility complex (MHC) act together to trigger celiac disease. For now, most of the analysis is based on static crystal structures. And the detailed information about these structures based on energetic interaction is still lacking. Here, we took four types of celiac disease-related MHC-peptide-TCR structures from three patients to perform computational alanine scanning calculations using the molecular mechanics generalized born surface area (MM/GBSA) approach combined with a recently developed interaction entropy (IE) method to identify the key residues on TCR, peptide, and MHC. Our study aims to shed some light on the interaction mechanism of this complex protein interaction system. Based on detailed computational analysis and mutational calculations, important binding interactions in these triple-interaction complexes are analyzed, and critical residues responsible for TCR/pMHC recognition pattern in HLA-DQ8-associated celiac disease are presented. These detailed analysis and computational result should help shed light on our understanding of the celiac disease and the development of the medical treatment.

Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits. PP2A can exist in nearly 100 different subunit combinations in mammalian cells, dictating distinct localizations, substrates and regulatory mechanisms. PP2A is well established as a regulator of cell division, growth, and differentiation, and the roles of PP2A in cancer and various neurodegenerative disorders, such as Alzheimer's disease, have been reviewed in detail. This Review summarizes and discusses recent reports on NDDs associated with mutations of PP2A subunits and PP2A-associated proteins. We also discuss the potential impact of these mutations on the structure and function of the PP2A holoenzymes and the etiology of NDDs.

The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth.

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.

The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis.

Osteoarthritis (OA) is a common cause of chronic pain and disability. Regenerative therapies using mesenchymal stem cells (MSCs) provide an option for OA treatment as it could potentially regenerate the damaged cartilage. Bone marrow, adipose tissue and synovium are common MSC sources. The aim is to compare the therapeutic effect of MSCs from bone marrow, adipose tissue and synovium; combining its differentiation potential and accessibility, to decide the optimal source of MSCs for the treatment of knee OA. A comparison of preclinical and clinical studies using MSCs has been made with regard to treatment outcomes, isolation procedure and differentiation potential. All types of MSCs are effective at improving the clinical and structural condition of OA patients, but the longevity of the treatment, i.e. an effect that is maintained for at least 2 years, cannot be guaranteed. This review highlighted great variations in selection criteria and culture expansion conditions of MSCs between the literature and clinical trials. It also emphasised a substantial diversity and lack of consistency in the assessment mythology of clinical outcome after completion of MSC therapies procedures. A more cohesive methodology is required to evaluate the outcome of MSC treatments using quantitative and standardised frameworks in order to be able to directly compare results. Larger population of patients are recommended to assess the quality of MSC when designing studies and clinical trials to reaffirm the efficacy of MSC treatment prior to and within the clinical trials and follow up studies.

Calculation of hot spots for protein-protein interaction in p53/PMI-MDM2/MDMX complexes.

The recently developed MM/GBSA_IE method is applied to computing hot and warm spots in p53/PMI-MDM2/MDMX protein-protein interaction systems. Comparison of the calculated hot (>2 kcal/mol) and warm spots (>1 kcal/mol) in P53 and PMI proteins interacting with MDM2 and MDMX shows a good quantitative agreement with the available experimental data. Further, our calculation predicted hot spots in MDM2 and MDMX proteins in their interactions with P53 and PMI and they help elucidate the interaction mechanism underlying this important PPI system. In agreement with the experimental result, the present calculation shows that PMI has more hot and warm spots and binds stronger to MDM2/MDMX. The analysis of these hot and warm spots helps elucidate the fundamental difference in binding between P53 and PMI to the MDM2/MDMX systems. Specifically, for p53/PMI-MDM2 systems, p53 and PMI use essentially the same residues (L54, I61, Y67, Q72, V93, H96, and I99) of MDM2 for binding. However, PMI enhanced interactions with residues L54, Y67, and Q72 of MDM2. For the p53/PMI-MDMX system, p53 and PMI use similar residues (M53, I60, Y66, Q71, V92, and Y99) of MDMX for binding. However, PMI exploited three extra residues (M61, K93, and L98) of MDMX for enhanced binding. In addition, PMI enhanced interaction with four residues (M53, Y66, Q71, and Y99) of MDMX. These results gave quantitative explanation on why the binding affinities of PMI-MDM2/MDMX interactions are stronger than that of p53-MDM2/MDMX although their binding modes are similar. © 2018 Wiley Periodicals, Inc.

Effect of mismatch on binding of ADAR2/GluR-2 pre-mRNA complex.

RNA editing plays an important role in realizing the full potential of a given genome. Different from RNA splicing, RNA editing fine-tunes the sequence of RNA by changing only one or two nucleotides. A-I editing [deamination of adenosine (A) to create inosine (I)] is best characterized in mammals and occurs in the regions of double-stranded RNA (dsRNA). Adenosine deaminases acting on RNA (ADARs) are members of a family of enzymes involved in A-I deamination editing in numerous mRNA and pre-mRNA transcripts. Experimental study shows that ADAR2 selectively edits the R/G site, while ADAR1 edits more promiscuously at several other adenosines. How ADAR2 selects specific sites for deamination is poorly understood. Mismatches have been suggested to be important factors that allow the ADAR2 to achieve specific deamination. Using molecular dynamic simulation, we studied the effect of mismatch on binding stability of the dsRNA/ADAR2 complex. By comparison of two binding domains of ADAR2, we found that ADAR2 dsRBM2 (second binding domain of ADAR2) does not bind well with mismatch reversed GluR-2 RNA. When mismatch is reversed, dsRBM2 of ADAR2 slides along the RNA duplex in the simulation. Detailed structural analysis indicates that the minor groove width of dsRNA and global shape of RNA may play an important role in the specific reading mechanism of ADAR2.