Toward Cluster Materials with Ordered Structures via Self-Assembly of Heterocluster Janus Molecules.

Cluster materials have attracted much attention because of their unique chemical and physical properties, hitherto unseen in bulk materials. Inspired by the lipid self-assembly principle, a series of heterocluster Janus molecules (HCJMs) with atomic precision have been rationally designed and synthesized by connecting different clusters via covalent bonds for the construction of nanomaterials and nano-objects. Due to their amphiphilicity, HCJMs self-assemble into cluster-containing nanomaterials or nano-objects with versatile ordered structures beyond those observed in conventional crystals. Their hybrid composition and nanoscale size are also greatly advantageous in the study of their fine structure by electron microscopy techniques, and enable their formation mechanisms to be unraveled. Finally, the influence of the characteristics of the HCJMs on the structure and properties of the self-assembled nano-objects are explored comprehensively. This synthesis strategy will promote further development of cluster materials with advanced functions via rational molecular design toward the construction of hierarchical nanostructures via molecular self-assembly.

Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult.

There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform in vivo functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human CTNNB1mt and zebrafish tcf7l2 or murine Myc together with krasv12 in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by krasv12 expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention.Significance: These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg Cancer Res; 78(19); 5548-60. ©2018 AACR.

Self-Assembly of Achiral Shape Amphiphiles into Multi-Walled Nanotubes via Helicity-Selective Nucleation and Growth.

Soft nanotubes are normally constructed from chiral amphiphiles through helical self-assembly. Yet, how to self-assemble achiral molecules into nanotubes is still a challenge. Here, we report the nanotube construction with achiral shape amphiphiles through helical self-assembly and also unravel the formation mechanisms. The amphiphiles have a dumbbell shape and are composed by covalently linking three achiral moieties together: two unlike clusters and an organic tether. The difference in polarity between the unlike clusters drives the amphiphiles to self-assemble into single- and multi-walled nanotubes as well as intermediates. Analysis of the key intermediates unravels the self-assembly mechanism of helicity-selective nucleation and growth. Meanwhile, direct visualization of the individual clusters in the ribbons displays a two-dimensional deformed hexagonal lattice. Thus, we speculate that it is the lattice deformation that creates anisotropic tension along different directions of the ribbon which further results in the formation of helical ribbons towards nanotubes by amphiphiles.

Creating Quasi Two-Dimensional Cluster-Assembled Materials through Self-Assembly of a Janus Polyoxometalate-Silsesquioxane Co-Cluster.

Clusters are an important class of nanoscale molecules or superatoms that exhibit an amazing diversity in structure, chemical composition, shape, and functionality. Assembling two types of clusters is creating emerging cluster-assembled materials (CAMs). In this paper, we report an effective approach to produce quasi two-dimensional (2D) CAMs of two types of spherelike clusters, polyhedral oligomeric silsesquioxanes (POSS), and polyoxometalates (POM). To avoid macrophase separation between the two clusters, they are covalently linked to form a POM-POSS cocluster with Janus characteristics and a dumbbell shape. This Janus characteristics enables the cocluster to self-assemble into diverse nanoaggregates, as conventional amphiphilic molecules and macromolecules do, in selective solvents. In our study, we obtained micelles, vesicles, nanosheets, and nanoribbons by tuning the n-hexane content in mixed solvents of acetone and n-hexane. Ordered packing of clusters in the nanosheets and nanoribbons were directly visualized using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) technique. We infer that the increase of packing order results in the vesicle-to-sheet transition and the change in packing mode causes the sheet-to-ribbon transitions. Our findings have verified the effectivity of creating quasi 2D cluster-assembled materials though the cocluster self-assembly as a new approach to produce novel CAMs.

Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth.

Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924-36. ©2016 AACR.

Tube-graft-Sheet Nano-Objects Created by A Stepwise Self-Assembly of Polymer-Polyoxometalate Hybrids.

In this work, we report the preparation of complex nano-objects by means of a stepwise self-assembly of two polymer-polyoxometalate hybrids (PPHs) in solution. The PPHs are designed and synthesized by tethering two linear poly(ε-caprolactone)s (PCL) of different molecular weights (MW) on a complex of a Wells-Dawson-type polyoxometalate (POM) cluster and its countraions. The higher MW PCL-POM self-assembled into nanosheets, while the lower MW PCL-POM assembled into nanotubes just by altering the ratio of water in the DMF-water mixed solvent system. The two nano-objects have a similar membrane structure in which a PCL layer is sandwiched by the two POM-based complex layers. The PCL layer in the nanosheets is semicrystalline, while the PCL layer in the nanotubes is amorphous. We further exploited this MW-dependence to self-assemble the nanotubes on the nanosheet edges to create complex tube-graft-sheet nano-objects. We found that the nanotubes nucleate on the four {110} faces of the PCL crystal and then further grow along the crystallographic b-axis of the PCL crystal. Our findings offer hope for the further development of nano-objects with increasing complexity.

A Filled-Honeycomb-Structured Crystal Formed by Self-Assembly of a Janus Polyoxometalate-Silsesquioxane (POM-POSS) Co-Cluster.

Clusters with diverse structures and functions have been used to create novel cluster-assembled materials (CAMs). Understanding their self-assembly process is a prerequisite to optimize their structure and function. Herein, two kinds of unlike organo-functionalized inorganic clusters are covalently linked by a short organic tether to form a dumbbell-shaped Janus co-cluster. In a mixed solvent of acetonitrile and water, it self-assembles into a crystal with a honeycomb superstructure constructed by hexagonal close-packed cylinders of the smaller cluster and an orderly arranged framework of the larger cluster. Reconstruction of these structural features via coarse-grained molecular simulations demonstrates that the cluster crystallization and the nanoscale phase separation between the two incompatible clusters synergistically result in the unique nano-architecture. Overall, this work opens up new opportunities for generating novel CAMs for advanced future applications.

A customizable stochastic state point process filter (SSPPF) for neural spiking activity.

Stochastic State Point Process Filter (SSPPF) is effective for adaptive signal processing. In particular, it has been successfully applied to neural signal coding/decoding in recent years. Recent work has proven its efficiency in non-parametric coefficients tracking in modeling of mammal nervous system. However, existing SSPPF has only been realized in commercial software platforms which limit their computational capability. In this paper, the first hardware architecture of SSPPF has been designed and successfully implemented on field-programmable gate array (FPGA), proving a more efficient means for coefficient tracking in a well-established generalized Laguerre-Volterra model for mammalian hippocampal spiking activity research. By exploring the intrinsic parallelism of the FPGA, the proposed architecture is able to process matrices or vectors with random size, and is efficiently scalable. Experimental result shows its superior performance comparing to the software implementation, while maintaining the numerical precision. This architecture can also be potentially utilized in the future hippocampal cognitive neural prosthesis design.

Langmuir and Langmuir-Blodgett films of hybrid amphiphiles with a polyoxometalate headgroup.

A hybrid was at first synthesized by a postfunctionalization of an aminomethane trisalkoxo-functionalized Anderson-type polyoxometalate (POM) encapsulated by three tetrabutylammonium ions using a 3,5-bis(tetradecyloxy)benzoic acid by amidation. Then the three TBA(+) counter cations were programmatically replaced by protons (H(+)) following a molecule-to-amphiphile conversion. In this way one hybrid and three POM-containing hybrid amphiphiles (PCHAs) were acquired by adjusting the number (n) of TBA(+) ions and number (3 - n) of H(+) ions (n = 3, 2, 1, and 0). These compounds can be spread onto a water surface to form a Langmuir monolayer film at the air-water interface. Surface pressure-molecular area measurements exhibit the TBA(+) (H(+)) number playing an important role in the forming ability and stability of Langmuir monolayer films. Also, the Langmuir-Blodgett (LB) technique has been used to transfer the monolayer film onto solid supports to fabricate solid multilayer films. It was found that the PCHA with three H(+) ions had the best Langmuir film-forming ability and thus formed stable LB films with a two-dimensional ordered structure. Our findings are instructive in fabricating and using solid films of the amphiphiles with POM headgroups.

POM-organic-POSS cocluster: creating a dumbbell-shaped hybrid molecule for programming hierarchical supramolecular nanostructures.

We report the construction of dumbbell-shaped hybrid molecules for programming their hierarchical supramolecular nanostructures through a synergetic self-assembly. Our first dumbbell-shaped hybrid molecule is a POM-organic-POSS cocluster produced by covalently coupling a POM cluster and a POSS cluster together through an organic tether. Structural analyses demonstrated a highly ordered lamellar morphology with a 4.9 nm periodicity, indicating a strong thermodynamic force driving a nanoscale phase separation of the POM and POSS blocks. The POM clusters were arranged in an orderly fashion within the POM-containing layer with a 1.38 nm periodicity because of fixed shape and size of the cluster. This investigation provides in-depth understanding of how to construct hierarchical supramolecular nanostructures at a nanoscale less than 5 nm by manipulating and controlling the topological shape of hybrid molecules.

Polyoxometalate-biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics.

Some polyoxometalate (POM) clusters have demonstrated attractive anticancer properties. Unfortunately, their cytotoxicity upon normal cell is one of fateful side effects obstructing their further clinic application as inorganic drugs. In this communication, we report a new approach to create hybrid drugs potentially for cancer therapeutics. At first, the POM cluster bioconjugates were created by attaching the bioactive ligands on an amine grafted POM via simple amidation reaction. The cytotoxicity study with breast cancer cells (MCF-7 and MDA-MB-231) and non-cancerous breast epithelial cell (MCF-10A) showed that rationally selected ligands with cancer-cell targeting ability on POM-biomolecule conjugates can impart enhanced anti-tumor activity and selectivity, thus representing a new concept to develop novel POM-biomolecule hybrid drugs with the potential synergistic effect: increased bioactivity and lower side effect.

Macromolecule-to-amphiphile conversion process of a polyoxometalate-polymer hybrid and assembled hybrid vesicles.

We report our findings on the macromolecule-to-amphiphile conversion process of a polyoxometalate-polymer hybrid and the assembled hybrid vesicles formed by aggregation of the hybrid amphiphile. The polyoxometalate-polymer hybrid is composed of a polyoxometalate (POM) cluster, which is covered by five tetrabutylammonium (Bu(4)N(+)) countercations, and a polystyrene (PS) chain. Through a cation-exchange process the Bu(4)N(+) countercations can be replaced by protons to form a hybrid amphiphile composed of a hydrophilic, protonated POM cluster and a hydrophobic PS chain. By implementing a directed one-dimensional diffusion and analyzing the diffusion data, we confirmed that the diffusion of solvated protons rather than macromolecules or aggregates is the key factor controlling the conversion process. Once the giant hybrid amphiphiles were formed, they immediately assembled into kinetically favored vesicular aggregates. During subsequent annealing these vesicular aggregates were transformed into thermodynamically stable vesicular aggregates with a perfect vesicle structure. The success in the preparation of the POM-containing hybrid vesicles provides us with an opportunity of preparing POM-functionalized vesicles.

Reoperative Therapy of Complex Hypospadias / 实用儿科临床杂志

Objective To evaluate operative management of complex hypospadias.Methods Twenty-one cases with complex hypospadias were reviewed.Thiresch procedure at 12 cases were taken.Island scrotal septal flap urethroplasty at 7 cases.Snodgrass procedure at 1 case.Mathieu procedure at 1 case.Results Fifteen cases were satisfied without fistula and stricture.Four cases with fistula,1 case with chordee,urethral meatus stricture in 1 case.Overall,the complication rate was 28.5%.Conclusions Selection of surgical procedure should according to the different case circumstance.It′s essential that reduce separative procedure,protect blood supply and carefully manipulation to improve successful rate.