Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)- paclitaxel nanoconjugate

The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the therapeutic index of paclitaxel (PTX). PGG-PTX is a modification of poly(L-glutamic acid)- paclitaxel conjugate (PGA-PTX) in which an additional glutamic acid has been added to each glutamic side chain in the polymer. PGG-PTX has higher water-solubility and faster dissolution than PGA-PTX. Unlike PGA-PTX, PGG-PTX self-assembles into nanoparticles, whose size remains in the range of 12–15 nm over the concentration range from 25 to 2,000 μg/mL in saline. Its critical micellar concentration in saline was found to be ~25 μg/mL. The potency of PGG-PTX when tested in vitro against the human lung cancer H460 cell line was comparable to other known polymer-PTX conjugates. However, PGG-PTX possesses lower toxicity compared with PGA-PTX in mice. The maximum tolerated dose of PGG-PTX was found to be 350 mg PTX/kg, which is 2.2-fold higher than the maximum tolerated dose of 160 mg PTX/kg reported for the PGA-PTX. This result indicates that PGG-PTX was substantially less toxic in vivo than PGA-PTX

Investigating the role of molecular motors on chromatin organization

In eukaryotes, chromatin carrying most of the genetic material and information is densely packed within the cell nucleus. To facilitate the proper functioning of numerous life-essential biological processes, it possesses multiple levels of packaging. On one hand, nucleosomes, as the most fundamental packing unit, controls the accessibility of chromatin through their positioning along the DNA sequence, where ATP-driven remodelers, DNA-binding proteins are known to play essential roles. On the other hand, the spatial organization of the genome, folding into compartments to harbor the functional regions, is also impacted by these non-equilibrium motor activities. Therefore, we carried out theoretical and computational investigations to unveil the role of molecular motors on chromatin organization in both one-dimensional and three-dimensional levels. In one dimension, we showed that the effect of remodel- ing enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions, when using a perturbation theory. We further constructed a unifying model to illustrate the construction of nucleosome positioning pattern during transcription. In three dimensions, we realized the conventional and inverted compartment distribution of chromatin with the interplay between active motors and passive interactions.Ph.D

Theory of Active Chromatin Remodeling

Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-Templated processes. ATP driven remodeling enzymes are known to be crucial for its establishment in vivo, but their nonequilibrium nature has hindered the development of a unified theoretical framework for nucleosome positioning. Using a perturbation theory, we show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Numerical simulations support the accuracy of the theory in predicting both kinetic and steady-state quantities, including the effective temperature and the radial distribution function, in biologically relevant regimes. The energy landscape view emerging from our study provides an intuitive understanding for the impact of remodeling enzymes in either reinforcing or overwriting intrinsic signals for nucleosome positioning, and may help improve the accuracy of computational models for its prediction in silico.National Institutes of Health (Grant 1R35GM133580-01

On the role of transcription in positioning nucleosomes.

Nucleosome positioning is crucial for the genome's function. Though the role of DNA sequence in positioning nucleosomes is well understood, a detailed mechanistic understanding on the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a heterogeneous distribution of +1 nucleosomes, caused by a tug-of-war between two types of remodeling enzymes, is essential for reproducing their density profiles. In particular, while positioning enzymes are known to remodel the +1 nucleosome and align it toward the transcription start site (TSS), spacer enzymes that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well- and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species

Weighted-elite-memory mechanism enhances cooperation in social dilemmas

The issue of how to enhance cooperation has been a hot topic of research in evolutionary games for a long time. A mechanism is proposed to facilitate the cooperation behavior of evolutionary groups on networks in three game models, including prisoner's dilemma, snowdrift game, and stag hunt game. The core of the mechanism lies in: 1) Each player has a length of memory and uses the information of the elite in the memory span to update its strategy. 2) Each player has the chance to game with a certain neighbor more than once in each round. 3) The accumulative payoff of a player consists of two parts, one from playing with elites in memory length and another from playing with current neighbors, and a weight is introduced to adjust these two parts. The findings of the simulation demonstrate that a small weight can significantly enhance cooperation in three typical social dilemmas. Furthermore, the level of cooperation increases at first and then stays stable as the memory length increases

betaNTI

The phylogenetic dissimilarity (beta NTI) of colonist and locally extinct species to the resident species

Data from: Nitrogen fertilization, not water addition, alters plant phylogenetic community structure in a semi-arid steppe

1. Anthropogenic environmental changes, such as nitrogen (N) enrichment and alteration in precipitation regimes, significantly influence ecosystems worldwide. However, we know little about whether and how these changes alter the phylogenetic properties of ecological communities. 2. Based on a seven-year field experiment in the temperate semi-arid steppe of Inner Mongolia, China, we investigated the influence of increased N and precipitation on plant phylogenetic structure and phylogenetic patterns of species colonization and extinction. 3. Our study demonstrated that N and water addition influenced different aspects of plant community structure. Water addition increased plant species richness by preventing species extinction and facilitating species colonization, without altering community phylogenetic structure. By contrast, N addition did not alter species richness, but promoted the colonization of species distantly related to the residents, changing community phylogenetic structure from being neutral to overdispersion. We also found evidence for abundance-based extinction where rarer species were at greater risk of extinction, and functional-based species extinction where shorter-statured plants and shallower-rooted plants were at greater risk of extinction. 4. Synthesis. Our study provides the first experimental evidence that plant phylogenetic community structure responds differently to different aspects of global changes. Importantly, the colonization of non-resident species, rather than the extinction of resident species, contributed predominantly to changes in plant community phylogenetic structure in response to N amendment. Our findings highlight the importance of considering species phylogenetic relationships for a more complete understanding of anthropogenic influences on ecological communities

Anlotinib affects systemic lipid metabolism and induces lipid accumulation in human lung cancer cells

Abstract Background Anlotinib has demonstrated encouraging clinical outcomes in the treatment of lung cancer, soft tissue sarcoma and thyroid carcinoma. Several clinical studies have shown a relationship between anlotinib treatment and the occurrence of hyperlipidemia. The fundamental mechanisms, however, are still largely unclear. Here, the effect of anlotinib on lipid metabolism in an animal model and human cancer cells was evaluated and the role of lipid metabolism in the antitumor efficacy of anlotinib was investigated. Methods The C57BL/6 J mouse model as well as A549 and H460 human lung cancer cell lines were used to examine the impact of anlotinib on lipid metabolism both in vivo and in vitro. Levels of triglycerides, high-density lipoprotein, low-density lipoprotein (LDL), and total cholesterol in serum or cell samples were determined using assay kits. The expression levels of crucial genes and proteins involved in lipid metabolism were measured by quantitative RT-PCR and Western blotting. Furthermore, exogenous LDL and knockdown of low-density lipoprotein receptor (LDLR) were used in H460 cells to investigate the relevance of lipid metabolism in the anticancer efficacy of anlotinib. Results Anlotinib caused hyperlipidemia in C57BL/6 J mice, possibly by downregulating hepatic LDLR-mediated uptake of LDL cholesterol. AMP-activated protein kinase and mammalian target of rapamycin inhibition may also be involved. Additionally, anlotinib enhanced sterol response element binding protein 1/2 nuclear accumulation as well as upregulated LDLR expression in A549 and H460 cells, which may be attributable to intracellular lipid accumulation. Knockdown of LDLR reduced intracellular cholesterol content, but interestingly, anlotinib significantly improved intracellular cholesterol accumulation in LDLR-knockdown cells. Both exogenous LDL and LDLR knockdown decreased the sensitivity of cells to anlotinib. Conclusions Anlotinib modulates host lipid metabolism through multiple pathways. Anlotinib also exerts a significant impact on lipid metabolism in cancer cells by regulating key transcription factors and metabolic enzymes. In addition, these findings suggest lipid metabolism is implicated in anlotinib sensitivity

phylogeny

Phylogenetic tree for the 58 species that were observed in the experimental area