Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy

Background: Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD. Methods: Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks. Results: Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral mu CT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P <0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treatedmice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P <0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice. Conclusions: Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.Peer reviewe

Small RNA AvrA Regulates IscR to Increase the Stress Tolerances in SmpB Deficiency of Aeromonas veronii

The superbacteria Aeromonas veronii displays not only a strong pathogenicity but also the resistance to nine kinds of antibiotics, resulting in the economic losses and health hazards. Small Protein B (SmpB) plays an important role in protein quality control, virulence, and stress reactions. Transcriptomic data revealed that expressions of the type IV pilus assembly and type VI secretion system (T6SS) proteins were downregulated in SmpB deficiency, indicating that the virulence of A. veronii might be attenuated. Although SmpB deletion decreased colonization in the mouse spleen and liver, LD50 of the smpB mutant was not altered as expected, compared with the wild type. Further, the transcriptomic and quantitative RT-PCR analyses showed that the combination of the downregulated AvrA and the upregulated iron-sulfur protein activator IscR, mediated the oxidative tolerance in smpB deletion. Next a reporter plasmid was constructed in which the promoter of iscR was applied to control the expression of the enhanced green fluorescent protein (eGFP) gene. When the reporter plasmid was co-expressed with the AvrA expression into E. coli, the relative fluorescence intensity was decreased significantly, suggesting that AvrA bound to iscR mRNA by base pairing, which in turn relieved the inhibition of iscR and intensified the downstream iron-sulfur proteins. Collectively, the smpB mutant exhibited an attenuated virulence in mice and enhanced tolerances to oxidative stress. This study demonstrates the complexity of gene regulation networks mediated by sRNA in systems biology, and also reflects the strong adaptability of superbacteria A. veronii in the process of evolution

Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy

Background: Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD.Methods: Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks.Results: Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral mu CT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treatedmice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice.Conclusions: Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders

Posterior hemivertebra resection without internal fixation in the treatment of congenital scoliosis in very young children

ObjectiveTo retrospectively analyze the feasibility and efficacy of posterior hemivertebra resection without internal fixation in the treatment of congenital scoliosis in very young children.MethodsSixteen cases of very young children with congenital scoliosis treated at our hospital from April 2000 to July 2019 were collected, including 8 cases of each sex, all of whom had type I/III congenital scoliosis and were operated on at a median (interquartile range) of 9.00 (7.75) months (range, 0.5–48 months) of age. All cases underwent posterior hemivertebra resection without internal fixation and wore orthopedic braces or plaster undershirts for more than six months after surgery, with a mean follow-up of 94.31 ± 65.63 months (range, 36–222 months).ResultsCoronal plane: the preoperative Cobb angle for the segmental curve was 39.50 ± 9.70° compared to postoperative (19.19 ± 8.56°) and last follow-up (14.94 ± 12.11°) (both P &lt; 0.01); the preoperative Cobb angle for the main curve was 34.19 ± 14.34° compared to postoperative (17.00 ± 11.70°) and last follow-up (17.56 ± 16.31°) (both P &lt; 0.01); the preoperative Cobb angle of the proximal compensated curve was 14.88 ± 9.62° compared to postoperative (7.88 ± 4.66°) and last follow-up (8.38 ± 8.36°) (both P &lt; 0.05); and the preoperative Cobb angle of the distal compensated curve was 13.50° (10.50°) (range, 4°–30°) compared with postoperative 4.50° (9.25°) (range, −3° to 25°) and final follow-up 5.50° (9.50°) (range, −3° to 33°) (both P &lt; 0.01). Sagittal plane: the difference in the preoperative Cobb angle was 10.00° (14.00°) (range, −31° to 41°) for segmental kyphosis compared to postoperative 14.00° (24.50°) (range, −6° to 46°) and last follow-up 17.00° (22.55°) (range, −40° to 56°), and these were not statistically significant (both P &gt; 0.05). There was a tendency for the thoracolumbar kyphosis to worsen and the lumbosacral kyphosis to improve during the follow-up period.ConclusionPosterior hemivertebra resection without internal fixation is a feasible treatment for type I/III congenital scoliosis in very young children, but the correction of the sagittal deformity of the thoracolumbar spine is not satisfactory, and postoperative external fixation may require further improvement

Characteristics of peritumoral pseudocapsule in small renal cell carcinoma and its influencing factors

Abstract Background The aim of this study was to investigate the peritumoral pseudocapsule (PC) status and identify the factors influencing PC status in small renal cell carcinoma (RCCs). Methods A total of 147 patients with small RCC (≤4 cm) who had undergone tumor enucleation (TE) were assigned into three groups according to PC status: complete PC, PC absence, and PC invasion. Computed tomography (CT) imaging and clinicopathological features were compared among the three groups. Univariate and multivariate analyses were performed to identify factors associated with incomplete PC. Results The number of patients with complete PC, PC absence, and PC invasion was 87 (59%), 20 (14%), and 40 (27%), respectively. Compared with the other two groups, tumors with complete PC were most common in clear cell RCC (CCRCC) and showed a hyperenhancement pattern (92%) and clear boundary (63%) on CT scanning images (p < 0.001). PC absence was most common in female patients (50%), whereas PC invasion was more common in male patients (85%) (p = 0.017). The tumor diameter in the PC absence group (2.24 ± 0.93 cm) was shorter compared with that of the complete PC group (2.88 ± 0.76 cm) and PC invasion group (3.16 ± 0.64 cm) (p < 0.001). Univariate and multivariate analysis showed that hypoenhancement pattern, unclear boundary, and non‐CCRCC subtype were independent risk factors of incomplete PC. Conclusions Hypoenhancement pattern, unclear boundary, and non‐CCRCC subtype were significant predictors of incomplete PC in small RCCs. It remains to be established whether TE is an appropriate procedure for patients with incomplete PC

Preparation and Characterization of Biodegradable Composited Films Based on Potato Starch/Glycerol/Gelatin

The use of plastics is resisted worldwide. Therefore, finding alternatives to plastic packaging products is an urgent issue. This work was dedicated to the preparation of biodegradable composited films with potato starch, glycerol, and gelatin. The formulation of the biodegradable film was first optimized via response surface methodology combined with the multi-index comprehensive evaluation method that considered physical properties (thickness, water solution (WS), tensile strength (TS) and elongation at break (E%)) and barrier property (light transmittance (T%)). Results indicated that the optimal conditions were 2.5% starch, 2.0% glycerol, and 1.5% gelatin (based on water). The optimized film presented excellent properties with TS of 4.47 MPa, E% of 109.91%, WS of 43.64%, and T% of 41.21% at 500 nm, and the comprehensive evaluation score of the composite film was 28.68. Moreover, a model verification experiment was further conducted, which proved that the predicted value highly matched experimental values, indicting the credibility and accuracy of the model. The resulting films were further characterized on the basis of rheological measurements, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The rheological measurements proved that the film-forming solution exhibited low shear viscosity and non-Newtonian fluid behavior. FTIR and SEM revealed excellent compatibility among starch, glycerol, and gelatin. Hence, the resulting optimized film may be expected to provide theoretical basis and technical support for the food packing industry

Selective delignification of poplar wood with a newly isolated white-rot basidiomycete Peniophora incarnata T-7 by submerged fermentation to enhance saccharification

Abstract Background Pretreatment is a critical step required for efficient conversion of woody biomass into biofuels and platform chemicals. Fungal pretreatment is regarded as one of the most promising technology for woody biomass conversion but remains challenging for industrial application. The exploration of potential fungus strain with high efficient delignification and less processing time for woody biomass pretreatment will be valuable for development of biorefinery industry. Here, a newly isolated white-rot basidiomycete Peniophora incarnate T-7 was employed for poplar wood pretreatment. Results The chemical component analysis showed that cellulose, hemicellulose and lignin from poplar wood declined by 16%, 48% and 70%, respectively, after 7 days submerged fermentation by P. incarnate T-7. Enzymatic saccharification analysis revealed that the maximum yields of glucose and xylose from 7 days of P. incarnate T-7 treated poplar wood reached 33.4% and 27.6%, respectively, both of which were enhanced by sevenfold relative to the untreated group. Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD) and pyrolysis gas chromatography–mass spectrometry (Py-GC/MS) characterization confirmed that lignocellulosic structure of poplar wood was largely broken by P. incarnate T-7, including delignification and de-crystalline of cellulose. Meanwhile, lignin component of poplar wood was selectively degraded by P. incarnate T-7, and G-type unit of lignin was preferentially attacked by the strain. Furthermore, quantitative proteomic analysis revealed that a considerable amount of lignocellulolytic enzymes were detected in the secretory proteins of P. incarnate T-7, especially with high abundance of lignin-degrading enzymes and hemicellulases. Combination of quantitative proteomic with transcriptomic analysis results showed that most of those lignocellulolytic enzymes were highly upregulated on poplar wood substrate compared to glucose substrate. Conclusions This study showed that P. incarnate T-7 could selectively delignify poplar wood by submerged fermentation with short time of 7 days, which greatly improved its enzymatic saccharification efficiency. Our results suggested that P. incarnate T-7 might be a promising candidate for industrial woody biomass pretreatment

Antifungal activity of an artificial peptide aptamer SNP-D4 against Fusarium oxysporum

Fusarium oxysporum f. sp. cubense (FOC4) is a pathogen of banana fusarium wilt, which is a serious problem that has plagued the tropical banana industry for many years. The pathogenic mechanism is complex and unclear, so the prevention and control in agricultural production applications is ineffective. SNP-D4, an artificial peptide aptamer, was identified and specifically inhibited FOC4. To evaluate the efficacy of SNP-D4, FoC4 spores were treated with purified SNP-D4 to calculate the germination and fungicide rates. Damage of FOC4 spores was observed by staining with propidium iodide (PI). Eight proteins of FOC4 were identified to have high affinity for SNP-D4 by a pull-down method combined with Q-Exactive mass spectrometry. Of these eight proteins, A0A5C6SPC6, the aldehyde dehydrogenase of FOC4, was selected as an example to scrutinize the interaction sites with SNP-D4. Molecular docking revealed that Thr66 on the peptide loop of SNP-D4 bound with Tyr437 near the catalytic center of A0A5C6SPC6. Subsequently 42 spore proteins which exhibited associations with the eight proteins were retrieved for protein-protein interaction analysis, demonstrating that SNP-D4 interfered with pathways including ‘translation’, ‘folding, sorting and degradation’, ‘transcription’, ‘signal transduction’ and ‘cell growth and death’, eventually causing the inhibition of growth of FOC4. This study not only investigated the possible pathogenic mechanism of FOC4, but also provided a potential antifungal agent SNP-D4 for use in the control of banana wilt disease

Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma

ABSTRACT Background The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age‐dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC. Methods The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity. Results When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression‐free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin‐related modifier (SUMO)‐specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC‐TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC‐TFE3 tRCC. Conclusions Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC‐TFE3 fusion protei

Forest degradation contributes more to carbon loss than forest cover loss in North American boreal forests

International audienc