Mutation of Basic Residues R283, R286, and K288 in the Matrix Protein of Newcastle Disease Virus Attenuates Viral Replication and Pathogenicity.

The matrix (M) protein of Newcastle disease virus (NDV) contains large numbers of unevenly distributed basic residues, but the precise function of most basic residues in the M protein remains enigmatic. We previously demonstrated that the C-terminus (aa 264-313) of M protein interacted with the extra-terminal (ET) domain of chicken bromodomain-containing protein 2 (chBRD2), which promoted NDV replication by downregulating chBRD2 expression and facilitating viral RNA synthesis and transcription. However, the key amino acid sites determining M's interaction with chBRD2/ET and their roles in the replication and pathogenicity of NDV are not known. In this study, three basic residues-R283, R286, and K288-in the NDV M protein were verified to be responsible for its interaction with chBRD2/ET. In addition, mutation of these basic residues (R283A/R286A/K288A) in the M protein changed its electrostatic pattern and abrogated the decreased expression of endogenic chBRD2. Moreover, a recombinant virus harboring these mutations resulted in a pathotype change of NDV and attenuated viral replication and pathogenicity in chickens due to the decreased viral RNA synthesis and transcription. Our findings therefore provide a better understanding of the crucial biological functions of M's basic residues and also aid in understanding the poorly understood pathogenesis of NDV.

Radially Inwardly Aligned Hierarchical Porous Carbon for Ultra-Long-Life Lithium-Sulfur Batteries.

Rational design of hollow micro- and/or nano-structured cathodes as sulfur hosts has potential for high-performance lithium-sulfur batteries. However, their further commercial application is hindered because infusing sulfur into hollow hosts is hard to control and the interactions between high loading sulfur and electrolyte are poor. Herein, we designed hierarchical porous hollow carbon nanospheres with radially inwardly aligned supporting ribs to mitigate these problems. Such a structure could aid the sulfur infusion and maximize sulfur utilization owing to the well-ordered pore channels. This highly organized internal carbon skeleton can also enhance the electronic conductivity. The hollow carbon nanospheres with further nitrogen-doping as the sulfur host material exhibit good capacity and excellent cycling performance (0.044 % capacity degradation per each cycle for 1000 cycles).

S100A16 promotes cell proliferation and metastasis via AKT and ERK cell signaling pathways in human prostate cancer.

S100A16 is a member of the S100 calcium-binding protein family. It is overexpressed in many types of tumors and associated with proliferation, migration, and invasion; however, its function in human prostate cancer is unresolved. Our objective was to determine its effects and the underlying pathways of S100A16 in prostate cancer tissues and cells. We measured S100A16 expression by quantitative real-time polymerase and Western blotting in eight matched prostate cancer and adjacent normal tissues, and in three prostate cancer cell lines, DU-145, LNCaP, and PC-3, compared to a normal prostate epithelial cell line PrEC. DU-145 cells stably overexpressing S100A16 and PC-3 cells with S100A16 knockdown were established by transfection with S100A16 overexpression plasmid or shRNAs. Invasion, migration, and proliferation were analyzed by transwell assay, wound healing, and colony formation assays, respectively. Western blotting and invasion assays were performed to determine expressions and activation of AKT, ERK, p21, and p27. S100A16 was significantly overexpressed in both prostate cancer tissues and cells lines compared to normal controls (P < 0.05). Overexpression of S100A16 significantly promoted invasion, migration, and proliferation in prostate cancer cells in vitro, whereas silencing S100A16 showed the converse effects (P < 0.05). Furthermore, overexpression of S100A16 activated cell signaling proteins AKT and ERK and downregulated tumor suppressors p21 and p27. Specific inhibitors, LY294002 and PD98059, suppressed activation of AKT and ERK, which attenuated DU-145 cell clone formation and invasion induced by S100A16 overexpression. S100A16 may promote human prostate cancer progression via signaling pathways involving AKT, ERK, p21, and p27 downstream effectors. Our findings suggest that S100A16 may serve as a novel therapeutic or diagnostic target in human prostate cancer.

Two ghrelin receptor agonists for adults with malnutrition: a systematic review and meta-analysis.

BACKGROUND: Ghrelin receptor agonists have been established to be important in ameliorating the nutritional conditions in patients with malnutrition. However, some studies have reported inconsistent results. We aimed to coalesce the available evidence on the efficacy of ghrelin receptor agonists for the treatment of malnutrition. METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE for relevant articles published through March 2016. Studies comparing the efficacy of ghrelin receptor agonists versus placebo in malnourished patients were eligible for inclusion. RESULTS: A total of 12 studies involving 1377 patients were included. Compared with placebo, ghrelin receptor agonists could increase the energy intake (standard mean difference [SMD] 2.67, 95% confidence interval [CI] 1.48 to 3.85, P < 0.001), lean body mass (weighted mean difference [WMD] 0.25 kg, 95% CI 0.07 to 0.42, P = 0.006), fat mass (WMD 0.92 kg, 95% CI 0.05 to 1.8, P = 0.038), and grip strength (WMD 0.31 kg, 95% CI 0.207 to 0.414, P < 0.001) of patients with malnutrition. CONCLUSION: Our analysis indicated that ghrelin receptor agonists could improve the poor nutritional state of malnourished patients by increasing their energy intake, ameliorating their irregular body composition and improving their grip strength. However, these results might be less conclusive due to the limited sample sizes and one potential publication that has not been released.

Role of p53 in preadipocyte differentiation.

Insulin resistance, diabetes and many kinds of cancers are common in overweight and obese individuals. The tumor suppressor p53 is important in securing genetic stability, but its role in the regulation of metabolic processes and cell differentiation remains unclear. We have investigated the role of p53 in adipocyte differentiation. Using 3T3-L1 cells, a mouse embryonic fibroblast preadipocyte model and DIO rat model, p53 expression and function during adipocyte differentiation were investigated. p53 expression increased on the second and fourth day of adipocyte differentiation and decreased thereafter. Its overexpression in 3T3-L1 preadipocytes markedly reduced adipogenesis and marker gene expression. p53 activity was weakened in DIO rat abdominal adipose tissue because of an decreased expression of its activated phosphorylated form. In contrast, p53 knockout enhanced adipogenesis and the expression of marker genes, but significantly reduced insulin-stimulated Akt phosphorylation. These results indicate that p53 partly suppresses preadipocyte differentiation and adipogenesis by regulating adipocyte gene expression and Akt signaling.

S100A16 inhibits osteogenesis but stimulates adipogenesis.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) have the capacity to differentiate into osteoblasts and adipocytes. Bone marrow adipogenesis exerts an inhibitory effect on osteogenesis, which leads to osteoporosis. S100A16, a novel member of the S100 family, is ubiquitously expressed, and markedly enhances adipogenesis. The aim of this study was to demonstrate, in the mouse BM-MSC model, whether S100A16 significantly stimulates adipogenic, rather than osteogenic differentiation. The overexpression of S100A16 led to a significant increase in Oil Red O staining (a marker of adipocyte differentiation) but a decrease in Alizarin Red S staining (a marker of osteoblast differentiation). In contrast, reducing the expression of S100A16 resulted in minimal Oil Red O staining but increased Alizarin Red S staining. During differentiation into osteoblasts, RUNX2 expression increased fourfold in the S100A16(KO+/-) BM-MSCs, but only increased by approximately 1.5-fold in the S100A16(TG+/+) BM-MSCs. And BMP2 occurred in the same changes. Upon induction of BM-MSC differentiation into adipocytes, peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α expression were significantly higher in the cells overexpressing S100A16 protein but lower in the cells with reduced expression of S100A16 protein, compared with the control cells, which were BM-MSCs derived from C57/BL6. S100A16 increased PPARγ promoter luciferase activity and decreased RUNX2 promoter luciferase activity. ERK1/2 phosphorylation was stimulated during osteogenesis, whereas p-JNK phosphorylation was increased by stimulation of adipogenesis. Our results suggest that S100A16 inhibits osteogenesis but stimulates adipogenesis by increasing the transcription of PPARγ and decreasing the transcription of RUNX2. The ERK1/2 pathway is involved in the regulation of osteogenesis whereas the JNK pathway is involved in adipogenesis.

Multifunctionality of matrix protein in the replication and pathogenesis of Newcastle disease virus: A review.

As an important structural protein in virion morphogenesis, the matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to be a nuclear-cytoplasmic trafficking protein and plays essential roles in viral assembly and budding. In recent years, increasing lines of evidence have indicated that the M protein has obvious influence on the pathotypes of NDV, and the interaction of M protein with cellular proteins is also closely associated with the replication and pathogenicity of NDV. Although substantial progress has been made in the past 40 years towards understanding the structure and function of NDV M protein, the available information is scattered. Therefore, this review article summarizes and updates the research progress on the structural feature, virulence and pathotype correlation, and nucleocytoplasmic transport mechanism of NDV M protein, as well as the functions of M protein and cellular protein interactions in M's intracellular localization, viral RNA synthesis and transcription, viral protein synthesis, viral immune evasion, and viral budding and release, which will provide an in-depth understanding of the biological functions of M protein in the replication and pathogenesis of NDV, and also contribute to the development of effective antiviral strategies aiming at blocking the early or late steps of NDV lifecycles.

Modeling and exploring the coordination relationship between green infrastructure and land use eco-efficiency: an urban agglomeration perspective.

In limited land space, improving the construction of infrastructure with ecological services can help to achieve the goal of promoting land use eco-efficiency (LUEE). In view of this, this study constructed interactive coordination relationship model of green infrastructure (GI) and LUEE that involves entropy method model, super-efficiency slack-based measure (SBM) model with undesirable outputs, and coupling coordination degree model. The interactive coordination relationship model can help to study and reveal the mechanisms of interaction and the coordination relationship between GI and LUEE from a land benefit and ecological perspective. We took the Beijing-Tianjin-Hebei urban agglomeration as the study area. The results showed that the assessment results of GI showed a decreasing trend from 2000 to 2020. LUEE in different cities displayed obvious variability with efficiency values ranging from 0.5666 to 2.4437. The relationship between GI and LUEE is in the stage of uncoordinated development in 53.8% of cities, mainly concentrated in the eastern and southern parts of the study area. The unnatural human activities are the critical factors affecting interactive coupling coordination degree of LUEE and GI. It is clarified that the level of coordination relationship of the two can be used as an important indicator to judge the sustainable development of urban agglomerations. Intensive use of land, optimal connection of geographic information, and localization of policies would help improve the balance and coordination between the two. This study provides interesting research ideas and novel modeling approaches for the study of green and sustainable development of urban agglomerations.

Upregulated miR-146a Expression in Peripheral Blood Relates to Th17 and Treg Imbalance in Elder Rheumatoid Arthritis Patients.

BACKGROUND: The expression level of microRNA-146a (miR-146a) increased in peripheral blood and synovialis tissue of rheumatoid arthritis (RA) patient, and it may play an important role in the pathological process of RA. We investigated its possibility as a diagnostic marker and the correlation with T helper 17 (Th17) and Treg cells in elder RA patients. METHODS: Blood samples were collected from 38 active RA patients, 38 inactive RA patients, and 40 healthy controls. RNA expression levels of miR-146a were detected from the peripheral blood samples. The proportion of Th17 and Treg cells were analyzed, as well as their cell-specific transcription factor retinoic acid-related orphan receptor variant 2 (RORc) and forkhead box protein 3 (FOXP3). Furthermore, secretion of pre-inflammatory and anti-inflammatory factors was detected. Correlations between miR-146a and these factors were also analyzed. RESULTS: Compared with healthy control, expression levels of miR-146a in inactive and active groups were significantly higher, with the highest level in active group. The expression of miR-146a and the RA severity, Th17 cell ratio, RORc expression, IL-17 level showed a significant positive correlation, while it showed a significantly negative correlation with Treg cell ration, FOXP3 expression, and TGF-ß1 secretion. CONCLUSIONS: These results suggested that miR-146a may be used as a disease progression marker in the peripheral blood of elder RA patients.

Spatio-temporal evolution characteristics analysis and optimization prediction of urban green infrastructure: a case study of Beijing, China.

The reasonable layout of green infrastructure is conducive to the low-carbon, livable and high-quality sustainable development of cities. The framework of spatio-temporal evolution characteristics and prediction analysis of Urban Green Infrastructure (UGI) was constructed by integrating morphological spatial pattern analysis (MSPA) and CA-Markov in the study. We analyzed the spatio-temporal evolution characteristics of UGI in Beijing from 1990 to 2019, predicted its future change trend in 2030, and put forward the optimization scheme for the ecological network of UGI. The area change of UGI presented a "V" shape from 1990 to 2019 in Beijing, and the turning point was around 2009. Its spatial distribution revealed a significant heterogeneity. The comprehensive change rate index showed a "rising and then falling" trend from 1990 to 2019. Core with an area of over 1000 km2 had inclined "C" shape, connecting the north, west and south of the study area. Among the three prediction scenarios for 2030, the area of UGI under the ecological conservation priority scenario is the largest, accounting for 86.35% of the total area. The area of UGI under the economic development priority scenario is the smallest, accounting for 76.85%. The optimization of zoning and road network are effective measures to improve the connectivity of UGI in Beijing. This study is beneficial to extend the research ideas of UGI and promote sustainable urban development.

Efficacy and safety of traditional Chinese medicine rehabilitation program in the treatment of knee osteoarthritis: a randomized controlled trial protocol.

BACKGROUND: Knee osteoarthritis (KOA) is a common joint disease worldwide, and the main cause of pain and disability in the elderly. Due to increased aging and rates of obesity of the global population, the number of patients with KOA is expected to increase. To reduce the burden of KOA, effective and safe interventions should be developed to reduce pain and improve range of motion, functionality, and quality of life. The aim of the proposed randomized controlled study was to evaluate the efficacy and safety of a traditional Chinese medicine (TCM) rehabilitation therapy in the treatment of KOA. METHODS: This multicenter, randomized, double-blind, parallel group, placebo-controlled trial will include a total of 200 patients with KOA. The enrolled patients will be randomly divided into the experimental group (n=100) and control group (n=100). The experimental group will receive basic treatment plus TCM rehabilitation therapy, while the control group will receive basic treatment plus physiotherapy regimen. Primary endpoints will include clinical efficacy outcomes, visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index score, and Knee Outcome Survey Activities of Daily Living Scale score. The data will help determine whether TCM rehabilitation therapy is beneficial for the treatment of KOA. DISCUSSION: The results will provide high-quality guidance for the current clinical treatment of KOA, and provide patients with more options for symptom relief. The findings from this study may provide updated evidence concerning the efficacy and safety of TCM for patients with KOA.

Soybean protein-derived peptides inhibit inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPK-JNK and NF-kappa B activation.

This study aimed to determine the effect of soybean protein-derived peptides (SBP) on the inhibition of lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation. The mRNA of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), Lymphocyte Antigen 96 (LY96), and nuclear factor-κB (NF-κB) were detected with RT-qPCR. The concentrations of cytokines (TNF-α, IL-6, and IL-1ß) secreted were detected by ELISA Kit. The results indicated that SBP inhibited the inflammatory stress induced by LPS in RAW264.7 cells. Western blot analysis was used to examine this anti-inflammatory molecular mechanism. The findings showed that SBP impeded the increase of toll-like receptor 4 activity by restricting LY96, while also inhibiting the mitogen-activated protein kinase-c-Jun N-terminal kinase pathway in cells, as well as LPS-induced NF-κB activation caused by the degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα). Consequently, the release of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) was inhibited, preventing LPS-induced inflammation of RAW 264.7 cells. Therefore, this research highlighted the potential application of SBP in the development of anti-inflammatory foods that prevented inflammatory-immune diseases. PRACTICAL APPLICATIONS: Inflammation is the root cause of almost all pathology and is related to many human diseases, including arthritis, obesity, cancer and atherosclerosis. Therefore, the development of products that can regulate and intervene inflammation has a broad application prospect. Soybean protein and soybean peptide have many functional properties, including immunoregulation, anti-inflammatory, anti-oxidation and so on. However, there are still some shortcomings in the development of soy protein supplements, such as solubility and absorption. Compared with soybean protein, derived peptide is easy to digest, and has high solubility. As a good nutritional supplement, the nutritional support of soybean protein-derived peptides may help to reduce inflammation and improve the level of cytokines combined with drugs.

The protective effect of soybean protein-derived peptides on apoptosis via the activation of PI3K-AKT and inhibition on apoptosis pathway.

Soybean protein-derived peptides (SBP) are a rich source of various bioactive peptides with multiple health benefits. However, the prospective effects of SBP on human cells are still unclear. Therefore, this article investigated the effects of small molecular weight SBP on MG132-induced apoptosis in RAW264.7 cells. SBP inhibited MG132-induced apoptosis of RAW264.7 cells in a dose-dependent manner by flow cytometry. To further study its molecular mechanisms, Western blot analysis demonstrated that SBP could activate the PI3K-AKT pathway by increasing the phosphorylation of PI3K and AKT and inhibiting apoptosis pathway by downregulating the expressions of pro-apoptotic proteins of Bim, Bax, Fas, and Fasl and promoting the expressions of anti-apoptotic proteins of Bcl-xL and Bcl-2. These results indicated the protective effect of SBP on MG132-induced apoptosis in RAW264.7 cells.

SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer.

Re-programming of lipogenic signaling has been previously demonstrated to result in significant alterations in tumor cell pathology. Sterol regulatory element-binding protein 1 (SREBP-1) is a known transcription factor of lipogenic genes. Despite the fact that its functions in proliferation and apoptosis have been elucidated in recent studies, its role in tumor cell migration and invasion, particularly in breast cancer, remains unclear. In present study, the messenger RNA and protein expression levels of SREBP-1 in cancer tissues were observed to be overexpressed compared with those in matched para-cancerous tissues (P<0.01). SREBP-1 level was highly positively correlated with tumor differentiation (P<0.001), tumor-node-metastasis stage (P=0.044) and lymph node metastasis (P<0.001). High expression of SREBP-1 predicted poor prognosis in patients with breast cancer. Additionally, multivariate analysis revealed that SREBP-1 was an independent factor of 5-year overall and disease-specific survival in breast cancer patients (P<0.01). In vitro studies revealed that the suppression of SREBP-1 expression in both MDA-MB-231 and MCF7 cells significantly inhibited cell migration and invasion (P<0.01). The present data indicate that SREBP-1 plays a critical role in breast cancer migration and invasion, and may serve as a prognostic marker of this malignancy.

Estrogen suppresses adipogenesis by inhibiting S100A16 expression.

The aim of this study is to determine the effects of E2 on metabolic syndrome and the molecular mechanisms involving S100A16. Ovariectomized (OVX) rat models and mouse embryonic fibroblasts cell models were used. E2 loss in OVX rats induced body weight gain and central abdominal fat accumulation, which were ameliorated by E2 treatment under chow and high-fat diet (HFD) conditions. E2 decreased the expression of the adipocyte marker genes PPARγ, aP2, C/EBPα, and S100A16. E2 inhibited adipogenesis. Overexpression of S100A16 reversed the E2-induced adipogenesis effect. A luciferase assay showed that E2 inhibited the expression of S100A16. E2 treatment decreased body weight gain and central abdominal fat accumulation under both chow and HFD conditions. Also, E2 suppressed adipogenesis by inhibiting S100A16 expression.