Hamiltonian L-stability of Lagrangian Translating Solitons

In this paper, we compute the first and second variation formulas for the F-functional of translating solitons and study the Hamiltonian L-stability of Lagrangian translating solitons. We prove that any Lagrangian translating soliton is Hamiltonian L-stable.Comment: arXiv admin note: text overlap with arXiv:1312.775

SER14-RPN6 PHOSPHORYLATION MEDIATES THE ACTIVATION OF 26S PROTEASOMES BY CYCLIC AMP AND PROTECTS AGAINST CARDIAC PROTEOTOXIC STRESS IN MICE

A better understanding of how proteasome activity is regulated can facilitate the search for proteasome enhancement strategies for disease treatment. A cell culture study shows cAMP-dependent protein kinase (PKA) activates 26S proteasomes by phosphorylating Ser14 of RPN6 (pS14-RPN6), but this discovery and its physiological significance remain to be established in vivo. To test the hypothesis that pS14-RPN6 mediates the activation of proteasomes by PKA and reduces proteotoxicity in animals, two knock-in mouse models with Ser14 of endogenous Rpn6 mutated to either Ala (S14A) or Asp (S14D) to respectively block or mimic pS14-Rpn6 were created. In a PKA-dependent manner, cAMP augmentation increased pS14-Rpn6 and 26S proteasome activities in wild-type (WT) but not S14A embryonic fibroblasts (MEFs), adult cardiomyocytes (AMCMs), and mouse hearts. Basal 26S proteasome activities were significantly greater in the myocardium and AMCMs from S14D mice than those from WT mice. When coupled with transgenic mice expressing GFPdgn (a proven UPS substrate), significantly lower myocardial GFPdgn protein but not mRNA levels were observed in S14D::GFPdgn mice compared with littermate GFPdgn control mice. In CryABR120G mice, a model of cardiac proteotoxicity, basal myocardial pS14-Rpn6 was significantly lower compared with non-transgenic littermates at both 3 and 6 months of age, which was not always associated with reduction of other phosphorylated PKA substrates. Proteasomal degradation of CryABR120G was faster in cultured S14D neonatal mouse cardiomyocytes (NMCMs) than in WT NMCMs. Compared with CryABR120G mice, S14D::CryABR120G mice showed significantly greater myocardial proteasome activities, lower levels of total and K48-linked ubiquitin conjugates and of aberrant CryABR120G protein aggregates, less reactivation of fetal genes and cardiac hypertrophy, and delays in cardiac malfunction and premature death. This study establishes in animals that pS14-Rpn6 is responsible for the activation of 26S proteasomes by PKA and reduced pS14-Rpn6 is a key pathogenic factor in cardiac proteinopathy, thereby identifies a new therapeutic target to reduce cardiac proteotoxicity

PHYSIOLOGICAL FUNCTION OF FUS: AN RNA BINDING PROTEIN IN MOTOR NEURON DISEASE

FUS is an RNA binding protein implicated in the motor neuron disease— amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease). ALS is a fatal neurodegenerative disease characterized by progressive motor neuron death. Mutations in the FUS gene cause about 4% of familial ALS (FUS ALS). Mutated FUS protein mislocalizes from the motor neuron nucleus to the cytoplasm and forms inclusions in the cytoplasm. It is unclear how FUS mislocalization induces motor neuron dysfunction and degeneration. This dissertation research was designed to investigate the physiological functions of FUS in the nucleus, with a purpose to shed light on the pathogenesis of FUS ALS. Using biochemical and cell biology approaches, we revealed that there are two functionally distinct pools of FUS inside the nucleus. A portion of FUS is bound to active chromatin domains and is involved in gene transcription regulation. ALS mutations significantly decrease FUS chromatin binding. We further discovered chromatin binding requires FUS oligomerization, which is mediated by an intrinsically disordered QGSY (glutamine-glycine-serine-tyrosine) -rich region in FUS. Using confocal microscopy and an in vitro FUS oligomerization assay, we identified chromatin-associated nuclear RNAs as the trigger of FUS oligomerization. We further discovered that the RNA binding ability of FUS is also required for the cytoplasmic inclusion formation, which does not require the QGSY-rich region. By exchanging localizations of wild-type FUS and mutant FUS, we demonstrated that subcellular localization and RNAs play a more important role than ALS mutations in determining distinct FUS distribution and organization in different cellular compartments. By knocking down protein arginine methyltransferase gene and using methylation inhibitor treatment, we found that a post-translational modification of FUS—arginine methylation—can regulate FUS chromatin binding. Suppression of arginine methylation restored mutant FUS binding to active chromatin domains. Altogether, we revealed the distribution-related FUS physiological functions in the nucleus and identified a potential way to reverse the destructive effect of ALS mutations on wild-type FUS

The Bunsen reaction in the presence of organic solvent in H2S splitting cycle

This research project is a part of our endeavor to developing a new hydrogen sulfide (H2S) splitting cycle for hydrogen production. In view of that the Bunsen reaction is the key step for the overall efficiency, the objective of this research is to develop an effective and efficient process to carry out the Bunsen reaction in the presence of organic solvents. Organic solvents can help dissolve iodine crystal, lower the reaction temperature and reduce the corrosiveness accompanying the reaction. Through screening of the ordinary organic solvents, aromatic hydrocarbons stood out and toluene was used in this project. In order to study the Bunsen reaction rate in the presence of toluene, the iodine solubility in HI solution was extensively explored at room temperature. Although the iodine solubility in water is small (0.3404g/L at 25℃), it was found that the iodine solubility in HI solution increases greatly as the [HI] increases. At lower [HI] (0~0.238 M), the iodine solubility is linear to [HI] with a relationship of [iodine solubility] = 0.57[HI] + 0.0030; at higher [HI] (0.238 ~7.6 M), the relationship of the iodine solubility and [HI] conforms to [iodine solubility]/[HI] = 0.190[HI] + 0.58. In the second part, the iodine distribution behavior between HI solution and toluene phase was studied at room temperature. It was determined that the iodine distribution coefficient (D = [I2]HI solution/[I2]toluene) increases as the increase of [HI]. At lower [HI] (0~1.89 M), the distribution coefficient has a quadratic relationship with [HI] as D = 1.4027[HI]2 + 0.8638[HI] + 0.0088; at higher [HI] (1.89~7.54 M) the distribution coefficient is linear to [HI] with a relationship of D=5.5937[HI]-3.5632. On the basis of the above work, in a semi-batch reactor, the Bunsen reaction rate in the presence of toluene was measured. In a mixture of toluene and water, iodine prefers to stay in toluene phase. The Bunsen reaction was readily initiated by feeding SO2 into water phase. Experimental results indicated that the rate of the Bunsen reaction in the presence of toluene is equal to the molar flow rate of feeding SO2 when the iodine concentration is higher than a certain value. This specific value depends on the reaction conditions, such as the interface area between water and toluene phase, the dispersion efficiency and the flow rate of SO2

Statistical Methods for Deconvolution in Cancer Genomics

With the advance of deep sequencing techniques, intratumor heterogeneity becomes a prevalent confounding factor to tumor genomic profiling studies. The heterogeneous composition of a tumor tissue can potentially lead to false positive differential expression conclusions and influence patients’ clinical outcomes and therapeutic responses. Many deconvolution methods aiming to separate the subcomponent signals have been developed in the past decades, modeling the tumor genomic profiling as a linear combination of the abundance of the mixing components. In this dissertation, we characterize a two- components (tumor versus non-tumor) model and develop a Fast Tumor Deconvolution (FasTD) pipeline to address the heterogeneity issue. We build a semi-parametric regression- based framework utilizing raw measured gene expression values, and provide mixing proportions and individual component genomic profiles as outputs. We demonstrate our method and show it is more than a thousand times faster than several current probabilistic models. Both simulated data and real data applications are provided to demonstrate the effectiveness of our proposed method. Our method is then extended to deconvolve heterogeneous tumor samples with more than two subcomponents. The extended pipeline (FasTDK) can effectively deconvolve an unknown component in K-subcomponent mixtures provided with K-1 reference profiles.Doctor of Philosoph

Developing High-performance Thin-film Composite Membranes for Water Recycling and Reuse

Membrane-based separation technologies, as versatile platforms, have attracted considerable attention for water recycling and reuse, due to their ease of operation, high separation efficiency, excellent sustainability, relatively low energy consumption, and industrial viability. Among them, thin-film composite (TFC) membranes have been widely employed for the desalination of seawater and separation of small organic compounds. However, the state-of-the-art polyamide TFC membranes still suffer from the severe fouling and limited water permeability, which are mainly ascribed to their intrinsic surface hydrophobicity and uncontrollable interfacial polymerization process. To address the current challenges and limitations in TFC membranes, it is essential to develop new methodologies and design new functional materials for the fabrication of TFC membranes. In this research, a new strategy based on the bioinspired chemistry has been explored for the fabrication of TFC membranes. In the strategy, polydopamine-modified cellulose nanocrystals (CNCs) with substantial quinonoid active sties have been prepared through oxidative auto-polymerization of dopamine, which enable the subsequent crosslinking with polyethylenimine (PEI). Electrospun nanofiber mats (ENMs) produced from electrospinning has been employed as the supporting layer in order to enhance the membrane permeability. TFC membranes are fabricated with the modified CNCs as the active layer via facile vacuum filtration on ENMs followed by further cross-linking with PEI. The achieved ultrahigh pure water permeability (PWP), superior dye rejection, and remarkable salt permeation demonstrate its great potential for the effective separation of dye/salt mixtures and recovery of these valuable components. To expand the application of bioinspired chemistry in TFC membranes, a rapid co-deposition of dopamine with zwitterions (Z-DNMA) via covalent polymerization triggered by CuSO4/H2O2 has been further proposed to construct the thin film selective layer. The fabricated TFC membranes with the incorporated zwitterionic structure from Z-DNMA show enhanced surface hydrophilicity and superior fouling-resistant performance towards both typical hydrophobic contaminants (e.g., proteins) and organic molecules (e.g., organic dyes). In addition to the development of new strategies, a new diamine monomer featured with trimethylamine N-oxide (TMAO) structure, N,N-bis (3-aminopropyl)methylamine N-oxide (DNMAO), has been designed for the fabrication of polyamide TFC membranes via interfacial polymerization. Its charged group (N+-O-) is directly connected without extra atoms and has the typical characteristics of zwitterions. The fabricated TFC membranes show high water permeability, high dye/salt selectivity, and improved antifouling ability. Apart from the polyamide TFC membranes, zwitterionic triethanolamine-based (Z-TEOA) polyester TFC membranes have been also fabricated via interfacial polymerization in this research. Z-TEOA endows a typical sulfonbetaine (SB) -based zwitterionic structure, which is one of the most widely used zwitterions in the fabrication of membranes. The performance of the polyester TFC membranes has been systematically investigated on the purification of dye- and antibiotic-contaminated wastewaters. The results in this thesis demonstrate the promising application of bioinspired chemistry in the fabrication of TFC membranes for the treatment of organic compounds-contaminated wastewaters. Meanwhile, the new generation of zwitterions based on TMAO-derived structure shows a great potential for the modification of the conventional polyamide TFC membranes to alleviate fouling propensity. Furthermore, this research also highlights the promising application of zwitterionic-modified polyhydroxyl monomers in the fabrication of polyester TFC membranes to enhance fouling-resistant performance