A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud.

PurposePreaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown.MethodsA rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model.ResultsA novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression.ConclusionOur results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms

Long Non Coding RNA MALAT1 Promotes Tumor Growth and Metastasis by Inducing Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma

The prognosis of advanced oral squamous cell carcinoma (OSCC) patients remains dismal, and a better understanding of the underlying mechanisms is critical for identifying effective targets with therapeutic potential to improve the survival of patients with OSCC. This study aims to clarify the clinical and biological significance of metastasis-associated long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in OSCC. We found that MALAT1 is overexpressed in OSCC tissues compared to normal oral mucosa by real-time PCR. MALAT1 served as a new prognostic factor in OSCC patients. When knockdown by small interfering RNA (siRNA) in OSCC cell lines TSCCA and Tca8113, MALAT1 was shown to be required for maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion. Western blot and immunofluorescence staining showed that MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro. Meanwhile, both nucleus and cytoplasm levels of β-catenin and NF-κB were attenuated, while elevated MALAT1 level triggered the expression of β-catenin and NF-κB. More importantly, targeting MALAT1 inhibited TSCCA cell-induced xenograft tumor growth in vivo. Therefore, these findings provide mechanistic insight into the role of MALAT1 in regulating OSCC metastasis, suggesting that MALAT1 is an important prognostic factor and therapeutic target for OSCC

How to Achieve Efficiency and Accuracy in Discrete Element Simulation of Asphalt Mixture: A DRF-Based Equivalent Model for Asphalt Sand Mortar

The clump-based discrete element model is one of the asphalt mixture simulation methods, which has the potential to not only predict mixture performance but also simulate particle movement during compaction, transporting, and other situations. However, modelling of asphalt sand mortar in this method remains to be a problem due to computing capacity. Larger-sized balls (generally 2.0-2.36 mm) were usually used to model the smaller particles and asphalt binder, but this replacement may result in the mixture\u27s unrealistic volumetric features. More specifically, replacing original elements with equal volume but larger size particles will increase in buck volume and then different particle contacting states. The major objective of this research is to provide a solution to the dilemma situation through an improved equivalent model of the smaller particles and asphalt binders. The key parameter of the equivalent model is the diameter reduction factor (DRF), which was proposed in this research to minimize the effects of asphalt mortar\u27s particle replacement modelling. To determine DRF, the DEM-based analysis was conducted to evaluate several mixture features, including element overlap ratio, ball-wall contact number, and the average wall stress. Through this study, it was observed that when the original glued ball diameters are ranging from 2.00 mm and 2.36 mm, the diameter reduction factor changes from 0.82 to 0.86 for AC mixtures and 0.80 to 0.84 for SMA mixtures. The modelling method presented in this research is suitable not only for asphalt mixtures but also for the other particulate mix with multisize particles

Nutritional Components and Health Functions of Mung Bean and its Application in the Development of Plant-based Food

Mung bean is a characteristic minor grain crop and a traditional medicine and food homologous material in China, and an important dry pulse in the world. Mung bean is high in protein and starch and rich in non-starch polysaccharides, polyphenols, flavonoids and other nutritional components, making it a popular research object of healthy food and functional activity among grain crops. This paper reviewed the research progress of nutritional components, functional ingredients (polyphenols, polysaccharides, functional proteins or peptides) and health functions such as antioxidant, lipid-lowering and hypoglycemic activities of mung bean at home and abroad in recent years. Meanwhile, the research and industrial application of mung bean in new plant-based food were introduced, aiming to provide reference for mung bean research and application in the future under the theoretical framework of modern nutrition and food science

Characteristic Analysis from Excessive to Deficient Syndromes in Hepatocarcinoma Underlying miRNA Array Data

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for many diseases. In this study, the characteristics among excessive, excessive-deficient, and deficient syndromes of Hepatocellular carcinoma (HCC) were studied using miRNA array data. We first calculated the differentially expressed miRNAs based on random module t-test and classified three TCM syndromes of HCC using SVM method. Then, the weighted miRNA-target networks were constructed for different TCM syndromes using predicted miRNA targets. Subsequently, the prioritized target genes of upexpression network of TCM syndromes were analyzed using DAVID online analysis. The results showed that there are distinctly different hierarchical cluster and network structure of TCM syndromes in HCC, but the excessive-deficient combination syndrome is extrinsically close to deficient syndrome. GO and pathway analysis revealed that the molecular mechanisms of excessive-deficient and deficient syndromes of HCC are more complex than excessive syndrome. Furthermore, although excessive-deficient and deficient syndromes have similar complex mechanisms, excessive-deficient syndrome is more involved than deficient syndrome in development of cancer process. This study suggested that miRNAs might be important mediators involved in the changing process from excessive to deficient syndromes and could be potential molecular markers for the diagnosis of TCM syndromes in HCC

Establishment of an Experimental Breast Cancer ZHENG Model and Curative Effect Evaluation of Zuo-Jin Wan

Herbal formulas based on the traditional Chinese medicine (TCM) syndrome (ZHENG) have been used as alternative treatments for breast cancer. However, there is a lack of the experimental animal ZHENG model for the evaluation of the herbal formulas. In this study, we have established 4T1 mouse breast cancer with Liver Fire Invading Stomach Syndrome model (4T1 LFISS mice) and investigated the effects of the herbal formula, Zuo-Jin Wan (ZJW). Our results showed that 4T1 LFISS mice have the features of LFISS including irritability, loss of appetite, yellow urine, chow, and a tail hot. Compared to untreated 4T1 LFISS mice, ZJW significantly reduced tumor weight and volume (P<0.05), although it was weaker than Cisplatin. However, ZJW significantly increased the body weight and food intake of 4T1 LFISS mice and decreased serum ALT, AST, Cr, and BUN levels and ZHENG score (P<0.05), while Cisplatin reduced the food intake, and body weight and increased serum ALT, AST, Cr, and BUN levels in 4T1 LFISS mice. Our study has provided a mouse breast cancer ZHENG model and showed that ZJW suppresses tumor growth and improves LFISS and kidney and liver functions in the 4T1 LFISS mice

Practical use of variational principles for modeling water waves

This paper describes a method for deriving approximate equations for irrotational water waves. The method is based on a 'relaxed' variational principle, i.e., on a Lagrangian involving as many variables as possible. This formulation is particularly suitable for the construction of approximate water wave models, since it allows more freedom while preserving the variational structure. The advantages of this relaxed formulation are illustrated with various examples in shallow and deep waters, as well as arbitrary depths. Using subordinate constraints (e.g., irrotationality or free surface impermeability) in various combinations, several model equations are derived, some being well-known, other being new. The models obtained are studied analytically and exact travelling wave solutions are constructed when possible.Comment: 30 pages, 1 figure, 62 references. Other author's papers can be downloaded at http://www.denys-dutykh.com

Inhibitory Effects of PC-SPESII Herbal Extract on Human Breast Cancer Metastasis

Cancer metastasis is refractory to most forms of chemotherapy. Conventional and alternative drugs, such as Chinese herbal remedies, have been developed to target metastatic cancer cells. In this study, we investigated the effects of PC-SPESII, an herbal formulation, on the migration, invasion, and metastasis of an experimental human breast cancer cell line in vivo and in vitro. PC-SPESII suppressed pulmonary metastasis and tumor growth of MDA-MB-231 human breast cancer xenografts without affecting body weight, liver function, and kidney function. PC-SPESII also inhibited MDA-MB-231 cell migration and invasion in vitro in a dose-dependent manner. Based on ELISA analysis, secretion of MMP-2 and MMP-9, proteins associated with extracellular matrix degradation, was reduced in response to PC-SPESII treatment. Western blot analysis of whole-cell extracts revealed that the levels of proteolytic proteins associated with matrix and base membrane degradation (MMP-2, MMP-9, and uPA) were decreased and the levels of their endogenous inhibitors (TIMP1 and TIMP2) were increased. Moreover, the p38MAPK and SAPK/JNK signaling pathway, which stimulates proteolytic enzymes and matrix degradation, was inhibited by PC-PSESII. Remarkably, cotreatment with PC-PSESII and p38MAPK or SAPK/JNK inhibitors magnified the antimetastatic phenotype. Our results indicate that PC-PSESII impairs human breast cancer metastasis by regulating proteolytic enzymes and matrix dynamics through the p38MAPK and SAPK/JNK pathway