The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby controls nutrient sensing.

Nutrient sensing is a critical cellular process controlling metabolism and signaling. mTOR complex 1 (mTORC1) is the primary signaling hub for nutrient sensing and, when activated, stimulates anabolic processes while decreasing autophagic flux. mTORC1 receives nutrient status signals from intracellular amino acid sensors. One of these sensors, Sestrin-2, functions as an intracellular sensor of cytosolic leucine and inhibitor of mTORC1 activity. Genetic studies of Sestrin-2 have confirmed its critical role in regulating mTORC1 activity, especially in the case of leucine starvation. Sestrin-2 is known to be transcriptionally controlled by several mechanisms; however, the post-translational proteolytic regulation of Sestrin-2 remains unclear. Here, we explored how Sestrin-2 is regulated through the ubiquitin proteasome system. Using an unbiased screening approach of an siRNA library targeting ubiquitin E3 ligases, we identified a RING-type E3 ligase, ring finger protein 186 (RNF186), that critically mediates the Sestrin-2 ubiquitination and degradation. We observed that RNF186 and Sestrin-2 bind each other through distinct C-terminal motifs and that Lys-13 in Sestrin-2 is a putative ubiquitin acceptor site. RNF186 knockdown increased Sestrin-2 protein levels and decreased mTORC1 activation. These results reveal a new mechanism of E3 ligase control of mTORC1 activity through the RNF186-Sestrin-2 axis, suggesting that RNF186 inhibition may be a potential strategy to increase levels of the mTORC1 inhibitor Sestrin-2.

A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma.

Matrix metalloproteinase 9 (MMP-9) plays an important role in the progression of several types of cancer by increasing tumor growth, migration, invasion, and metastasis and is associated with poor disease prognosis. The possible prognostic value of MMP-9 in osteosarcoma has also been examined, but due to inconsistent results between studies, it has not been possible to draw firm conclusions. To clarify this issue, we conducted a meta-analysis of published studies to provide a comprehensive evaluation of the effect of high MMP-9 expression on the survival outcomes of osteosarcoma patients. Seven studies with a total of 339 patients with osteosarcoma were examined. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to evaluate the effect of MMP-9 expression on overall survival. Meta-analysis showed that patients with high MMP-9 expression were significantly associated with lower overall survival when compared to their counterparts with low or undetectable MMP-9 expression (OR=6.13, 95 % CI 3.45-10.89, P<0.001). Sensitivity analysis suggested the pooled OR was stable and not significantly changed when a single study was removed. The results from the systematic review and meta-analysis show that MMP-9 is an effective biomarker for predicting survival of patients with osteosarcoma.

Microarray expression profile of long noncoding RNAs in human osteosarcoma.

Long noncoding RNAs (lncRNAs) are pervasively transcribed and have a critical role in genome regulation. Alterations in the expression of several lncRNAs have been observed in some types of cancers; however, the contributions of lncRNAs to osteosarcoma remain unknown. Here, we describe the expression profile of lncRNAs in osteosarcomas compared with paired adjacent noncancerous tissue using microarray analysis. In our study, 25,733 lncRNAs were expressed in osteosarcoma; 403 lncRNAs were consistently over-regulated and 798 lncRNAs were consistently under-regulated in all samples analyzed (⩾2.0-fold, p<0.05). Quantitative real-time polymerase chain reaction (PCR) was used to validate six over-regulated and four under-regulated lncRNAs. Bioinformatic analysis (gene ontology analysis, pathway analysis and network analysis) was used for further research. Pathway analysis indicated that 32 pathways corresponded to under-regulated transcripts and that 34 pathways corresponded to over-regulated transcripts (p-value cut-off is 0.05). Our results are the first to reveal differentially expressed lncRNAs in osteosarcoma and suggest that lncRNAs may be novel candidate biomarkers for the diagnosis of osteosarcoma and potential targets for therapy.

Evaluation of the coordination between marine ecological environment protection and marine economic development in China.

Over the years, the development of marine economy has been an important component of coastal cities' total economic growth in China. Whether the coastal cities had paid enough attention to the coordination of marine economic development and ecological environment protection in the process of marine development activities needed to be evaluated accordingly. An index evaluation system for the coordination between marine ecological environment protection and marine economic development in coastal cities of China was established in this work by using the analytic hierarchy process. The statistical analysis results from 2006 to 2018 showed that much more attention had been paid on marine ecological environment protection since the year 2012 in China. The evaluated results showed that among all coastal provinces and cities, Shanghai and Shandong Provinces had the best coordination between marine economic development and marine ecological environment protection in the year 2016. Years of data showed that marine economic development and marine ecological environmental protection complement each other and promote each other. At the same time, the analysis results of this indicator evaluation system showed that marine ecological environment protection in China should further strengthen the protection by preventing and controlling marine pollution and carrying out ecological restoration.

Technical methodologies for the assessment of the impacts of reclamation projects on marine ecology.

The present article introduces the concept of ecological assessment of reclamation projects. In addition, we built a framework that considers structure, function, and ecosystem services for the assessment of the impact of reclamation projects on marine ecology. Moreover, this study explored different technical methods for the ecological assessment of reclamation projects, with an emphasis on those that evaluate the impacts of reclamation on marine ecosystems structure. The present research provides technical support for the recognition and diagnosis of marine ecology problems that are the result of reclamation projects, introduces a guideline for the development of ecological restoration projects, assists in protecting coastal wetland ecosystems, promotes the scientific and reasonable management and control of reclamation, and helps in maintaining the regional marine ecological security pattern.

Co-Occurrence Relationship and Stochastic Processes Affect Sedimentary Archaeal and Bacterial Community Assembly in Estuarine-Coastal Margins.

Sedimentary microorganisms play crucial roles in maintaining the functional stability of aquatic ecosystems. However, their taxonomic composition and assembly processes are not well known in estuarine−coastal margins because of their complex environment. We investigated microbial communities, co-occurrence relationships, and underlying mechanisms in 33 surface sediment samples collected in the Jiulong River Estuary and the Taiwan Strait to reveal their composition dynamics. The abundance, diversity, and composition of microorganisms demonstrated obvious spatial variables. Methanobacterium and Methanosarcina, as well as Candidatus_Nitrosopumilus and Nitrososphaeraceae were the main methanogenic and ammonia-oxidizing archaea, with an average abundance of more than 5.91% and 4.27%, respectively. Along with a salinity gradient increase, the relative abundance of methanogenic archaea (from 42.9% to 16.6%) contrasted with the trend of ammonia-oxidizing archaea (from 6.04% to 18.7%). The number of methanogenic archaea gradually decreased with increasing geographic distance (p < 0.05), whereas ammonia-oxidizing archaea showed no significant change (p > 0.05). In co-occurrence patterns, closer inter-taxa connections were observed among archaea−archaea and bacteria−bacteria than in archaea−bacteria, which indicated that coexistence within the same kingdom was greater than interaction between different kingdoms in shaping the community structure along the salinity gradient. Furthermore, null model analyses of the microbial community showed that undominated was the most prominent process, explaining over 44.9% of community variation, followed by heterogeneous selection and dispersal limitation, which contributed to 27.7% and 16.3%, respectively. We demonstrated that stochasticity, rather than determinism, regulates community assembly. These results further highlight that intra-kingdom co-occurrence and stochastic processes shape the structure and assembly of microbial communities in estuarine−coastal margins.

Numerical simulation of the impact of an integrated renovation project on the Maowei Sea hydrodynamic environment.

Integrated renovation projects are important for marine ecological environment protection. Three-dimensional hydrodynamics and water quality models are developed for the Maowei Sea to assess the hydrodynamic environment base on the MIKE3 software with high resolution meshes. The results showed that the flow velocity changed minimally after the project, decreasing by approximately 0.12 m/s in the east of the Maowei Sea area and increasing by approximately 0.01 m/s in the northeast of the Shajing Port. The decrease in tidal prism (~ 2.66 × 106 m3) was attributed to land reclamation, and accounted for just 0.86% of the pre-project level. The water exchange half-life increased by approximately 1 day, implying a slightly reduced water exchange capacity. Siltation occurred mainly in the reclamation and dredging areas, amounting to back-silting of approximately 2 cm/year. Reclamation project is the main factor causing the decrease of tidal volume and weakening the hydrodynamics in Maowei Sea. Adaptive management is necessary for such a comprehensive regulation project. According to the result, we suggest that reclamation works should strictly prohibit and dredging schemes should optimize in the subsequent regulation works.

Hypoxia-inducible factor-1 expression predicts osteosarcoma patients' survival: a meta-analysis.

Osteosarcoma, the most common primary bone malignancy, is characterized by easily relapsing and metastasizing. Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumorigenesis, affecting tumor metabolism, differentiation, angiogenesis, proliferation and metastasis, and has been found to be associated with survival in patients with osteosarcoma. The possible prognostic value of HIF-1 was investigated in many studies, but the results were inconsistent. We therefore conducted a meta-analysis to elucidate the correlation of HIF-1 expression, analyzed by immunohistochemistry in osteosarcoma tissues, with prognosis. The association degree was assessed by calculation of the hazard ratio (HR) and risk ratio (RR) with corresponding 95% confidence intervals (CIs). Follow-up information was available for 486 patients from 7 studies. The results showed that high HIF-1 expression was associated with a worse prognosis when compared to low or undetectable HIF-1 expression, with an HR of 3.67 (95% CI 2.24-5.99; p<0.001) for overall survival (OS) and an RR of 3.72 (95% CI 2.26-6.13; p<0.001) for OS. The RR of 2.55 for disease-free survival (DFS) did not show any obvious relationship between a high level of HIF-1 and DFS (95% CI 0.95-6.87; p = 0.064). The stability of this result was tested by sensitivity analysis and no significant change was detected. This meta-analysis suggests that HIF-1 is an effective prognostic biomarker to predict OS in patients with osteosarcoma.

MicroRNA screening identifies circulating microRNAs as potential biomarkers for osteosarcoma.

MicroRNAs (miRNAs) are a family of small non-protein coding RNAs, which regulate the expression of a wide variety of genes at the post-transcriptional level to control numerous biological and pathological processes. Various circulating miRNAs have been identified as potential diagnostic and prognostic biomarkers in multiple types of cancer and disease. The aim of the present study was to identify potential miRNA biomarkers for the early diagnosis and relapse prediction of osteosarcoma (OS). miRNA profiling was performed on serum from patients with osteosarcoma and healthy controls. All putative miRNAs were verified by reverse transcription-quantitative polymerase chain reaction analysis of 20 pre-therapeutic OS patients and 20 healthy individuals. The expression of miR-106a-5p, miR16-5p, miR-20a-5p, miR-425-5p, miR451a, miR-25-3p and miR139-5p was demonstrated to be downregulated in the serum of OS patients when compared with that of the healthy controls. Receiver-operating characteristic curve analyses indicated that these 7 miRNAs may be used as diagnostic biomarkers with the ability to discriminate between the healthy cohort and patients with OS. These results provide novel insights into the use of miRNAs in early blood screening for OS.

Screening for metastatic osteosarcoma biomarkers with a DNA microarray.

OBJECTIVE: The aim of this study was to screen for possible biomarkers of metastatic osteosarcoma (OS) using a DNA microarray. METHODS: We downloaded the gene expression profile GSE49003 from Gene Expression Omnibus database, which included 6 gene chips from metastatic and 6 from non-metastatic OS patients. The R package was used to screen and identify differentially expressed genes (DEGs) between metastatic and non-metastatic OS patients. Then we compared the expression of DEGs in the two groups and sub-grouped into up-regulated and down-regulated, followed by functional enrichment analysis using the DAVID system. Subsequently, we constructed an miRNA-DEG regulatory network with the help of WebGestalt software. RESULTS: A total of 323 DEGs, including 134 up-regulated and 189 down-regulated, were screened out. The up-regulated DEGs were enriched in 14 subcategories and most significantly in cytoskeleton organization, while the down-regulated DEGs were prevalent in 13 subcategories, especially wound healing. In addition, we identified two important miRNAs (miR-202 and miR-9) pivotal for OS metastasis, and their relevant genes, CALD1 and STX1A. CONCLUSIONS: MiR-202 and miR-9 are potential key factors affecting the metastasis of OS and CALD1 and STX1A may be possible targets beneficial for the treatment of metastatic OS. However, further experimental studies are needed to confirm our results.

P16INK4a overexpression and survival in osteosarcoma patients: a meta analysis.

Osteosarcoma is one of the most common primary bone malignancies. Although there is a significant improvement of survival on osteosarcoma patients in the past decades, treatment of osteosarcoma is still unsatisfactory for the development of pulmonary metastasis. The potential prognostic value of p16(INK4a) in osteosarcoma has been investigated, however, the results from different studies were somewhat controversial. To elucidate whether p16(INK4a) is indeed a prognostic factor of osteosarcoma, we conducted a meta-analysis of the published literatures to provide a comprehensive evaluation of the significance of p16(INK4a) expression in patients with osteosarcoma. Eight studies with a total of 354 patients with osteosarcoma were examined. The pooled odds ratio (OR) with corresponding 95% confidence interval (95% CI) was calculated to evaluate the effect of p16(INK4a) expression on overall survival. Meta-analysis showed that patients with high p16(INK4a) expression were significantly associated with favourable overall survival when compared to their counterparts with low or undetectable p16(INK4a) expression (OR = 0.270, 95% CI 0.162-0.451, P < 0.001). Sensitivity analysis suggested the pooled OR was stable and not significantly changed when a single study was removed. In conclusion, the results from this meta-analysis highlight that p16(INK4a) is an effective biomarker of survival in patients with osteosarcoma.

[Ultrasound measurement of fetal posterior fossa at 11 to 13⁺6 gestational weeks for screening open spina bifida].

OBJECTIVE: To establish the normal reference ranges of transabdominal ultrasound measurements of the posterior fossa structure in fetuses at 11 to 13⁺6 gestational weeks and explore their clinical value in screening open spina bifida (OSB). METHODS: Between January, 2013 and September, 541 randomly selected normal fetuses underwent nuchal translucency at the gestational age 11 to 13⁺6 weeks. The parameters of the posterior fossa were measured in mid-sagittal view of the fetal face and the axial view of the transverse cerebellum insonated through the anterior fontanel by transabdominal ultrasound to establish the normal reference ranges. The measurements were obtained from 3 fetuses with OSB for comparison with the reference ranges. RESULTS: In normal fetuses, the parameters of the posterior fossa measured in the two views showed no significant differences (P>0.05). Two high echogenic lines were observed in normal fetuses, as compared with one in fetuses with OSB representing the posterior border of the brain stem and the anterior border of the fourth ventricle. The line between the posterior border of the fourth ventricle and the anterior border of the cisterna magna was not displayed in fetuses with OSB. The anteroposterior diameters of the brain stem, the fourth ventricle, and cisterna magna all increased in positive correlation with the crown-lump length in normal fetuses. In the 3 OSB fetuses, the anteroposterior diameter of the brain stem exceeded the 95th percentile and the anteroposterior diameter of fourth ventrical-cisterner magena was below the 5th percentile of the reference range for CRL; the brain stem to fourth ventrical-cisterner magena anteroposterior diameter ratio was increased to above 1. CONCLUSION: The established normal reference ranges of the parameters of fetal posterior fossa may provide assistance in early OSB detection. The absence of the posterior border of the fourth ventricle and the anterior border of the cisterna magna and a brainstem to fourth ventrical-cisterner magena anteroposterior diameter ratio greater than 1 can be indicative of OSB at 11 to 13⁺6 gestational weeks.

[An approach to screen fetal agenesis of the corpus callosum at 11-13(+6) weeks].

OBJECTIVE: To detect structural changes in the brain in fetuses with agenesis of the corpus callosum (ACC) and holoprosencephaly (HPE) in the first trimester. METHODS: The ultrasound data were analyzed retrospectively in 620 normal singleton fetuses between 11 and 13(+6) gestational weeks, 5 fetuses diagnosed to have ACC, and 13 fetuses with HPE. The midbrain diameter (MD) and falx diameter (FD) were measured and their ratio (MD/FD) was calculated for comparative analysis. RESULTS: No significant difference was found in the MD, FD, and MD/FD ratio between fetuses with ACC and HPE (P>0.05). Compared to the normal fetuses, all the fetuses with ACC and HPE showed significantly increased mean MD and MD/FD ratio (P<0.05); 4 (80%) fetuses with ACC and 11 (84.6%) with HPE had a reduced FD. All the fetuses with ACC and HPE had MD/FD ratios greater than 1, which were below 1 in all the normal fetuses. CONCLUSION: In the first trimester, fetuses with ACC and HPE have measurable abnormalities in the midbrain and falx area of the brain, and these changes, represented by abnormal midsagittal MD, FD and their ratio, can be of value in detecting ACC or HPE in fetuses in the first trimester.

[An approach for integrated assessment of eco-risk in coastal waters based on catastrophe theory: taking Luoyuan Bay as a case].

Based on catastrophe theory, this paper established an index system and catastrophe progression model for the integrated assessment of eco-risk in coastal waters, including three risk types of "eutrophication-heavy metal pollution-organic pollution" and three dimensions of "water-sediment-organism". According to the related quality standards, a four-level evaluation standard of eco-risk (zero, low, medium, and high) was proposed, and by using the monitoring data of 2007 and 2009, an integrated assessment of the eco-risk in Luoyuan Bay was conducted. In 2007-2009, the spatial variation of the eco-risk in Luoyuan Bay had a downward trend from bayhead to baymouth, and the risk level in 2009 was overall lower than that in 2007. The key factor of the eco-risk in the Bay was eutrophication. The approach established in this paper could identify the spatiotemporal variation characteristics of eco-risk in coastal waters, and better reflect the key eco-risk factor, providing a basic approach for effective forecasting and early warning of eco-risk in coastal waters.