van der Waals Stacking-Induced Topological Phase Transition in Layered Ternary Transition Metal Chalcogenides

Novel materials with nontrivial electronic and photonic band topology are crucial for realizing novel devices with low power consumption and heat dissipation and quantum computing free of decoherence. Here, we theoretically predict a novel class of ternary transition metal chalcogenides that exhibit dual topological characteristics, quantum spin Hall insulators (QSHIs) in their two-dimensional (2D) monolayers and topological Weyl semimetals in their 3D noncentrosymmetric crystals upon van der Waals (vdW) stacking. Remarkably, we find that one can create and annihilate Weyl fermions and realize the transition between Type-I and Type-II Weyl fermions by tuning vdW interlayer spacing, providing the missing physical picture of the evolution from 2D QSHIs to 3D Weyl semimetals. Our results also show that these materials possess excellent thermodynamic stability and weak interlayer binding; some of them were synthesized two decades ago, implying their great potentials for experimental synthesis, characterization, and vdW heterostacking. Moreover, their ternary nature will offer more tunability for electronic structure by controlling different stoichiometry and valence charges. Our findings provide an ideal materials platform for realizing QSH effect and exploring fundamental topological phase transition and will open up a variety of new opportunities for two-dimensional materials and topological materials research.National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Award DMR-1419807)United States. Department of Energy. Division of Materials Sciences and Engineering (Award DE-SC0010526

Tissue-Engineered Trachea Consisting of Electrospun Patterned sc-PLA/GO-g-IL Fibrous Membranes with Antibacterial Property and 3D-Printed Skeletons with Elasticity

In this study, a tissue-engineered trachea, consisting of multilevel structural electrospun polylactide (PLA) membranes enveloping 3D-printed thermoplastic polyurethane (TPU) skeletons, was developed to create a mechanically robust, antibacterial and bioresorbable graft for the tracheal reconstruction. The study design incorporated two distinct uses of stereocomplex PLA: patterned electrospun fibers to enhance tissue integration compared to the random layered fibers, meanwhile possessing good antibacterial property; and 3D-printed TPU scaffold with elasticity to provide external support and protection. Herein, ionic liquid (IL)-functioned graphene oxide (GO) was synthesized and presented enhanced mechanical and hydrophilicity properties. More interesting, antibacterial activity of the GO-g-IL modified PLA membranes were proved by Escherichia coli and Staphylococcus aureus, showing superior antibacterial effect compared to single GO or IL. The synergistic antibacterial effect could be related to that GO break cytomembrane of bacteria by its extremely sharp edges, while IL works by electrostatic interaction between its cationic structures and electronegative phosphate groups of bacteria membranes, leading to the loss of cell electrolyte and cell death. Hence, after L929 fibroblast cells were seeded on patterned fibrous membranes with phenotypic shape, further effective cell infiltration, cell proliferation and attachment were observed. In addition, the tissue-engineered trachea scaffolds were implanted into rabbit models. The in vivo result confirmed that the scaffolds with patterned membranes manifested favorable biocompatibility and promoted tissue regeneration

Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer

PURPOSE: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors. METHODS: Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay. RESULTS: ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non- CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold. CONCLUSIONS: These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies

Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia

Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging “cancer methylome”. In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-β (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC

The genome and transcriptome of Japanese flounder provide insights into flatfish asymmetry

Flatfish have the most extreme asymmetric body morphology of vertebrates. During metamorphosis, one eye migrates to the contralateral side of the skull, and this migration is accompanied by extensive craniofacial transformations and simultaneous development of lopsided body pigmentation(1-5). The evolution of this developmental and physiological innovation remains enigmatic. Comparative genomics of two flatfish and transcriptomic analyses during metamorphosis point to a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways. We demonstrate that retinoic acid is critical in establishing asymmetric pigmentation and, via cross-talk with thyroid hormones, in modulating eye migration. The unexpected expression of the visual opsins from the phototransduction pathway in the skin translates illumination differences and generates retinoic acid gradients that underlie the generation of asymmetry. Identifying the genetic underpinning of this unique developmental process answers long-standing questions about the evolutionary origin of asymmetry, but it also provides insight into the mechanisms that control body shape in vertebrates.National Natural Science Foundation of China [31130057, 31461163005, 31530078, 31472269, 31472262, 31472273]; State 863 High Technology R&D Project of China [2012AA092203, 2012AA10A408, 2012AA10A403-2]; Education and Research of Guangdong Province [2013B090800017]; Taishan Scholar Climb Project Fund of Shandong of China; Taishan Scholar Project Fund of Shandong of China for Young Scientists; Shanghai Universities First-class Disciplines Project of Fisheries; Program for Professor of Special Appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning; Shanghai Municipal Science, Special Project on the Integration of Industryinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/publishedVersio

The Implications of Relationships between Human Diseases and Metabolic Subpathways

One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the “k-clique” subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN). Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue-specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play significantly differential roles on the diversity of diseases caused by the corresponding subpathway