Quiescent Adult Neural Stem Cells: Developmental Origin and Regulatory Mechanisms.

The existence of neural stem cells (NSCs) in the adult mammalian nervous system, although small in number and restricted to the sub-ventricular zone of the lateral ventricles, the dentate gyrus of the hippocampus, and the olfactory epithelium, is a gift of evolution for the adaptive brain function which requires persistent plastic changes of these regions. It is known that most adult NSCs are latent, showing long cell cycles. In the past decade, the concept of quiescent NSCs (qNSCs) has been widely accepted by researchers in the field, and great progress has been made in the biology of qNSCs. Although the spontaneous neuronal regeneration derived from adult NSCs is not significant, understanding how the behaviors of qNSCs are regulated sheds light on stimulating endogenous NSC-based neuronal regeneration. In this review, we mainly focus on the recent progress of the developmental origin and regulatory mechanisms that maintain qNSCs under normal conditions, and that mobilize qNSCs under pathological conditions, hoping to give some insights for future study.

RASSF1A inhibits epithelial-mesenchymal transition of gastric cancer cells by downregulating P-JNK.

Gastric cancer (GC) is one of the most common gastrointestinal tumors. In this study, we assessed the biological role of Ras association domain family 1 isoform A (RASSF1A) in GC cells. Expressions of RASSF1A and the relationship of RASSF1A with epithelial-mesenchymal transformation (EMT)-related proteins were assessed in five cell lines using Western blot. GC cells with RASSF1A overexpression were used to study sensitivity to cisplatin, migration, invasion, and the expression of EMT-associated biomarkers. GC cells showed profound downregulation of RASSF1A expression compared with normal human gastric mucosal cells. High RASSF1A expression was associated with increased overall survival. Overexpression of RASSF1A regulates GC cells activity and the expression of EMT-associated biomarkers. RASSF1A regulates E-cadherin and Vimentin through P-JNK pathway. Our results revealed that RASSF1A can inhibit the proliferation, migration, and invasion of GC cells via E-cadherin. Our study provides insights for further research on GC.

Effects of nitric acid rain stress on soil nitrogen fractions and fungal communities in a northern subtropical forest, China.

Acid rain has severely negatively impacted terrestrial ecosystems and biogeochemical cycles. However, the potential impacts of nitric acid rain (NAR) on soil nitrogen (N) fractions and fungal community diversity in northern subtropical forest soils remain largely unevaluated. In this study, treatments of NAR at pH = 4.5 (AR4.5), pH = 3.5 (AR3.5), and pH = 2.5 (AR2.5) were randomly sprayed in a typical Quercus acutissima Carruth. stand in northern subtropical China. The soil N fractions and soil fungal communities were analyzed after a 12-month experimental period. The results revealed that compared to the control, the soil total N (TN), microbial biomass N (MBN), hydrolysable ammonium N (HAN), amino-sugar N (ASN) and amino-acid N (AAN) contents decreased significantly by 19.61-13.07 %, 20.10-9.04 %, 60.41-28.87 %, 74.10-62.25 %, and 65.69-45.64 % under stronger acidity inputs (i.e., AR2.5 and AR3.5), respectively. Besides, the AR2.5 and AR3.5 treatments increased the α-diversity indices of soil fungal communities and altered the soil fungal community structure. Moreover, the NAR treatments represented an increase in the relative abundance of Ascomycota and Mortierellomycota and a decrease in that of Basidiomycota. Mortierella, Penicillium, and Tomentella can be used as indicator genera for changes in soil fungal community structures under NAR stress. Furthermore, AAN was the main environmental factor affecting soil fungal community at the phylum and genus levels. Cumulatively, findings from this research provide valuable insight into NAR's effects on N cycling and microbial communities in forest soils.

Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2.

Angiogenesis factors are widely known to promote tumor growth by increasing tumor angiogenesis in the tumor microenvironment, however, little is known whether their intracellular function is involved in tumorigenesis. Here we show that AGGF1 acts as a tumor suppressor by regulating p53 when acting inside tumor cells. AGGF1 antagonizes MDM2 function to inhibit p53 ubiquitination, increases the acetylation, phosphorylation, stability and expression levels of p53, activates transcription of p53 target genes, and regulates cell proliferation, cell cycle, and apoptosis. AGGF1 also interacts with p53 through the FHA domain. Somatic AGGF1 variants in the FHA domain in human tumors, including p.Q467H, p.Y469 N, and p.N483T, inhibit AGGF1 activity on tumor suppression. These results identify a key role for AGGF1 in an AGGF1-MDM2-p53 signaling axis with important functions in tumor suppression, and uncover a novel trans-tumor-suppression mechanism dependent on p53. This study has potential implications in diagnosis and therapies of cancer.

Inhibition of epithelial­mesenchymal transition in gastric cancer cells by miR­711­mediated downregulation of CD44 expression.

Gastric cancer is a common malignancy worldwide. The prognosis of early stage gastric cancer patients has significantly improved in recent years. However, in progressive stage gastric cancer patients, the prognosis remains relatively poor due to tumor metastases. In our previous study, we showed that the expression of miR­711 in gastric cancer tissues is low, and restoration of miR­711 inhibited the invasion and migration and the occurrence of epithelial­mesenchymal transition (EMT) in gastric cancer cells. Yet, the mechanisms involved in these processes remain unknown. In the present study, we demonstrated that miR­711­mediated downregulation of CD44 expression inhibited EMT of gastric cancer cells in vitro and in vivo by downregulating vimentin protein expression and upregulating E­cadherin protein expression through transfection, qRT­PCR and western blotting. Therefore, miR­711 may provide a promising target for EMT­related therapy for gastric cancer.

Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. When mutated, however, it causes Klippel-Trenaunay syndrome, a vascular disorder. In this study, we show that angiotensin II (AngII)-the major effector of the renin-angiotensin system and one of the most important regulators of the cardiovascular system-induces the expression of AGGF1 through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis. AngII significantly up-regulated the levels of AGGF1 mRNA and protein in HUVECs at concentrations of 10-40 µg/ml but not >60 µg/ml. AngII type 1 receptor (AT1R) inhibitor losartan inhibited AngII-induced up-regulation of AGGF1, whereas AT2R inhibitor PD123319 further increased AngII-induced up-regulation of AGGF1. Up-regulation of AGGF1 by AngII was blocked by NF-κB inhibitors, and p65 binds directly to a binding site at the promoter/regulatory region of AGGF1 and transcriptionally activates AGGF1 expression. AngII-induced endothelial tube formation was blocked by small interfering RNAs (siRNAs) for RELA (RELA proto-oncogene, NF-κB subunit)/p65 or AGGF1, and the effect of RELA siRNA was rescued by AGGF1. AngII-induced angiogenesis from aortic rings was severely impaired in Aggf1+/- mice, and the effect was restored by AGGF1. These data suggest that AngII acts as a critical regulator of AGGF1 expression through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis.-Si, W., Xie, W., Deng, W., Xiao, Y., Karnik, S. S., Xu, C., Chen, Q., Wang, Q. K. Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Application of ensemble surrogates and adaptive sequential sampling to optimal groundwater remediation design at DNAPLs-contaminated sites.

In this study, we aimed to develop an optimal groundwater remediation design for sites contaminated by dense non-aqueous phase liquids by using an ensemble of surrogates and adaptive sequential sampling. Compared with previous approaches, our proposed method has the following advantages: (1) a surrogate surfactant-enhanced aquifer remediation simulation model is constructed using a Gaussian process; (2) the accuracy of the surrogate model is improved by constructing ensemble surrogates using five different surrogate modelling techniques, i.e., polynomial response surface, radial basis function, Kriging, support vector regression, and Gaussian process; (3) we conducted comparisons and analyses based on 31 surrogate models derived from different combinations of the five surrogate modelling techniques; and (4) the reliability of the optimal solution was improved by implementing adaptive sequential sampling. The two proposed methods were applied to a hypothetical perchloroethylene-contaminated site in order to demonstrate their performance. The results showed that the best surrogate model integrated all five of the surrogate modelling methods, with an R2 value of 0.9913 and a root mean squared error of 0.0159, thereby demonstrating the advantage of using ensemble surrogates. In addition, the reliability of the optimization model solution was improved by adaptive sequential sampling, which avoided false solutions.

Conservative strategy-based ensemble surrogate model for optimal groundwater remediation design at DNAPLs-contaminated sites.

The surrogate-based simulation-optimization techniques are frequently used for optimal groundwater remediation design. When this technique is used, surrogate errors caused by surrogate-modeling uncertainty may lead to generation of infeasible designs. In this paper, a conservative strategy that pushes the optimal design into the feasible region was used to address surrogate-modeling uncertainty. In addition, chance-constrained programming (CCP) was adopted to compare with the conservative strategy in addressing this uncertainty. Three methods, multi-gene genetic programming (MGGP), Kriging (KRG) and support vector regression (SVR), were used to construct surrogate models for a time-consuming multi-phase flow model. To improve the performance of the surrogate model, ensemble surrogates were constructed based on combinations of different stand-alone surrogate models. The results show that: (1) the surrogate-modeling uncertainty was successfully addressed by the conservative strategy, which means that this method is promising for addressing surrogate-modeling uncertainty. (2) The ensemble surrogate model that combines MGGP with KRG showed the most favorable performance, which indicates that this ensemble surrogate can utilize both stand-alone surrogate models to improve the performance of the surrogate model.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro-oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

A novel approach to make homogeneous protease-stable monovalent streptavidin.

The interaction between the tetramer streptavidin and biotin is recognized as one of the strongest non-covalent associations. Owing to the tight and specific binding, the streptavidin-biotin system has been used widely for bimolecular labeling, purification, immobilization, and even for targeted delivery of therapeutics drugs. Here, we report a novel approach to make homogeneous monovalent tetramer streptavidin. The purified monovalent protein showed both thermal stability and protease stability. Unexpectedly, we found that two proteases, Proteinase K (PK) and Subtilisin (SU), can efficiently remove the His8-tag from the wild-type subunit without affecting the tetramer architecture of monovalent streptavidin, thus making it more homogeneous. In addition, crystallization was performed to assure the homogeneity of the monovalent protein prepared. Overall, monovalent streptavidin shows increased homogeneity and will likely be valuable for many future applications in a wide range of research areas.