Regulation of nuclear–cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt

Recent genome-wide association studies reveal that the FAM13A gene is associated with human lung function and a variety of lung diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary fibrosis. The biological functions of Fam13a, however, have not been studied. In an effort to identify novel substrates of B56-containing PP2As, we found that B56-containing PP2As and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. We show that Ser-322 phosphorylation acts as a molecular switch to control the subcellular distribution of Fam13a. Fam13a shuttles between the nucleus and cytoplasm. When Ser-322 is phosphorylated by Akt, the binding between Fam13a and 14-3-3 is enhanced, leading to cytoplasmic sequestration of Fam13a. B56-containing PP2As dephosphorylate phospho–Ser-322 and promote nuclear localization of Fam13a. We generated Fam13a-knockout mice. Fam13a-mutant mice are viable and healthy, indicating that Fam13a is dispensable for embryonic development and physiological functions in adult animals. Intriguingly, Fam13a has the ability to activate the Wnt pathway. Although Wnt signaling remains largely normal in Fam13a-knockout lungs, depletion of Fam13a in human lung cancer cells causes an obvious reduction in Wnt signaling activity. Our work provides important clues to elucidating the mechanism by which Fam13a may contribute to human lung diseases.     

EGFR-mediated G1/S transition contributes to the multidrug resistance in breast cancer cells

Despite the improvement of strategies against cancer therapy, the multidrug resistance (MDR)is the critical problem for successful cancer therapy. Recurrent cancers after initial treatment with chemotherapy are generally refractory to second treatments with these anticancer therapies. Therefore, it is necessary to elucidate the therapy-resistant mechanism for development of effective therapeutic modalities against tumors. Here we demonstrate a phase-specific chemotherapy resistance due to epidermal growth factor receptor (EGFR) in human breast cancer cells. Thymidine-induced G1-arrested cultures showed upregulated chemosensitivity, whereas S-phase arrested cells were more resistant to chemotherapeutic agents. Overexpression of EGFR promoted the MDR phenotypes in breast cancer cells via accelerating the G1/S phase transition, whereas depletion of EGFR exerted the opposite effects. Furthermore, CyclinD1, a protein related to cell cycle, was demonstrated to be involved in above EGFR-mediated effects since EGFR increased the expression of CyclinD1, and the specific RNA interference against CyclinD1 could primarily abolish the EGFR-induced MDR phenotypes. These data provide new insights into the mode by which MDR breast cancers evade cytoxic attacks from chemotherapeutic agents and also suggest a role for EGFR-CyclinD1 axis in this process.     

KNOCKDOWN OF ATPsyn‐b CAUSED LARVAL GROWTH DEFECT AND MALE INFERTILITY IN Drosophila

The ATPsyn‐b encoding for subunit b of ATP synthase in Drosophila melanogaster is proposed to act in ATP synthesis and phagocytosis, and has been identified as one of the sperm proteins in both Drosophila and mammals. At present, its details of functions in animal growth and spermatogenesis have not been reported. In this study, we knocked down ATPsyn‐b using Drosophila lines expressing inducible hairpin RNAi constructs and Gal4 drivers. Ubiquitous knockdown of ATPsyn‐b resulted in growth defects in larval stage as the larvae did not grow bigger than the size of normal second‐instar larvae. Knockdown in testes did not interrupt the developmental excursion to viable adult flies, however, these male adults were sterile. Analyses of testes revealed disrupted nuclear bundles during spermatogenesis and abnormal shaping in spermatid elongation. There were no mature sperm in the seminal vesicle of ATPsyn‐b knockdown male testes. These findings suggest us that ATPsyn‐b acts in growth and male fertility of Drosophila.     

Characterization of Transcriptional Repressor Gene MSX1 Variations for Possible Associations with Congenital Heart Diseases

Background

The human heart consists of several cell types with distinct lineage origins. Interactions between these cardiac progenitors are very important for heart formation. The muscle segment homeobox gene family plays a key role in the cell morphogenesis and growth, controlled cellular proliferation, differentiation, and apoptosis, but the relationships between the genetic abnormalities and CHD phenotypes still remain largely unknown. The aim of this work was to evaluate variations in MSX1 and MSX2 for their possible associations with CHD.

Methods

We sequenced the MSX1 and MSX2 genes for 300 Chinese Han CHD patients and 400 normal controls and identified the variations. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.

Results

Six variations rs4647952, rs2048152, rs4242182, rs61739543, rs111542301 and rs3087539 were identified in the MSX2 gene, but the genetic heterozygosity of those SNPs was very low. In contrast, the genetic heterozygosity of two variations rs3821949 near the 5’UTR and rs12532 within 3’UTR of the MSX1 gene was considerably high. Statistical analyses showed that rs3821949 and rs12532 were associated with the risk of CHD (specifically VSD).

Conclusions

The SNPs rs3821949 and rs12532 in the MSX1 gene were associated with CHD in Chinese Han populations.     

生物操纵理论与技术在富营养化湖泊治理中的应用

近年来,全球范围内湖泊富营养化问题日趋严重。以生物操纵理论为指导,采用水生食物网调控、改善水质、抑制藻类的生物修复方法,为解决这一问题提供了可行的途径。论文综述了生物操纵理论的产生、发展和应用,阐述了富营养化水体生态系统中肉食性鱼类、滤食性鱼类、浮游动物、沉水植物和细菌等的作用,并针对当前生物操纵技术应用中存在的差异性问题,提出了不同湖泊应根据其特性采取不同的组合技术并重点采取相应措施的建议。     

Joint Microbial and Metabolomic Network Estimation with the Censored Gaussian Graphical Model

Joint analysis of microbiome and metabolomic data represents an imperative objective as the field moves beyond basic microbiome association studies and turns towards mechanistic and translational investigations. We present a censored Gaussian graphical model framework, where the metabolomic data are treated as continuous and the microbiome data as censored at zero, to identify direct interactions (defined as conditional dependence relationships) between microbial species and metabolites. Simulated examples show that our method metaMint performs favorably compared to the existing ones. metaMint also provides interpretable microbe-metabolite interactions when applied to a bacterial vaginosis data set. R implementation of metaMint is available on GitHub.

     

The Intrinsic Role of Molecular Mass and Polydispersity Index in High-Performance Non-Fullerene Polymer Solar Cells

The degree of polymerization can cause significant changes in the blend microstructure and physical mechanism of the active layer of non-fullerene polymer solar cells, resulting in a huge difference in device performance. However, the diversity of stability issues, including photobleaching stability, storage stability, photostability, thermal stability, and mechanical stability, and more, poses a challenge for the degree of polymerization to comprehensively address the trade-off between device efficiency and stability and reasonably evaluate the application potential of polymer materials. Herein, a series of PM6 polymers with different weight-average molecular weights (M_w) and polydispersity index (PDI) are synthesized. The effects of the degree of PM6 polymerization on the efficiency and degradation behaviors of the photovoltaic systems based on Y6 as acceptor are investigated systematically. The findings regarding stability issues, together with the trade-offs in the efficiency-stability gap, formulate a complete guideline for the material design and performance evaluation in a way that relies much less on trial-and-error efforts.     

The broad-spectrum antibiofilm activity of amyloid-forming hexapeptides

Evidence suggests that short amyloid-forming peptides derived from bacterial proteomes have functional roles; however, the reported activities are diverse and the underlying mechanisms remain unclear. In this study, we simulated short amyloid-forming peptides from the amyloid-forming truncated protein C123 of Streptococcus mutans (S. mutans), studied their biological functions in microbial proliferation and biofilm formation, and further investigated the underlying mechanism. Fourteen hexapeptides were simulated, 13 of which were successfully synthesized. We found that the amyloid-forming hexapeptides (AFhPs) displayed efficient broad-spectrum antibiofilm activity against the Gram-positive bacteria S. mutans, Streptococcus sanguis and Staphylococcus aureus, Gram-negative bacteria Escherichia coli and fungus Candida albicans, by aggregating into rigid amyloid fibres agglutinating microbes, whereas the non-amyloid-forming hexapeptides (non-AFhPs) did not. The AFhPs did not kill microbes and showed little or no cytotoxicity. Furthermore, a set of AFhPs displayed broad-spectrum antibiofilm activity, regardless of its source. The microbial cell wall carbohydrates, peptidoglycan (PGN), lipoteichoic acid (LTA), glucan and zymosan A, mediated AFhP binding and triggered significant AFhP fibrillation. Although amyloid fibres agglutinated lipid membrane model – large unilamellar vesicles (LUVs) – and LUVs facilitated AFhP fibrillation, the roles of lipid membranes in AFhP antibiofilm activities remain to be elucidated. We highlight the potential use of AFhPs as novel antibiofilm agents.