Role of Map4k4 in Skeletal Muscle Differentiation: A Dissertation

Skeletal muscle is a complicated and heterogeneous striated muscle tissue that serves critical mechanical and metabolic functions in the organism. The process of generating skeletal muscle, myogenesis, is elaborately coordinated by members of the protein kinase family, which transmit diverse signals initiated by extracellular stimuli to myogenic transcriptional hierarchy in muscle cells. Mitogen-activated protein kinases (MAPKs) including p38 MAPK, c-Jun N terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) are components of serine/threonine protein kinase cascades that play important roles in skeletal muscle differentiation. The exploration of MAPK upstream kinases identified mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4), a serine/threonine protein kinase that modulates p38 MAPK, JNK and ERK activities in multiple cell lines. Our lab further discovered that Map4k4 regulates peroxisome proliferator-activated receptor γ (PPARγ) translation in cultured adipocytes through inactivating mammalian target of rapamycin (mTOR), which controls skeletal muscle differentiation and hypotrophy in kinase-dependent and -independent manners. These findings suggest potential involvement of Map4k4 in skeletal myogenesis. Therefore, for the first part of my thesis, I characterize the role of Map4k4 in skeletal muscle differentiation in cultured muscle cells. Here I show that Map4k4 functions as a myogenic suppressor mainly at the early stage of skeletal myogenesis with a moderate effect on myoblast fusion during late-stage muscle differentiation. In agreement, Map4k4 expression and protein kinase activity are declined with myogenic differentiation. The inhibitory effect of Map4k4 on skeletal myogenesis requires its kinase activity. Surprisingly, none of the identified Map4k4 downstream effectors including p38 MAPK, JNK and ERK is involved in the Map4k4-mediated myogenic differentiation. Instead, expression of myogenic regulatory factor Myf5, a positive mediator of skeletal muscle differentiation is transiently regulated by Map4k4 to partially control skeletal myogenesis. Mechanisms by which Map4k4 modulates Myf5 amount have yet to be determined. In the second part of my thesis, I assess the relationship between Map4k4 and IGF-mediated signaling pathways. Although siRNA-mediated silencing of Map4k4 results in markedly enhanced myotube formation that is identical to the IGF-induced muscle hypertrophic phenotype, and Map4k4 regulates IGF/Akt signaling downstream effector mTOR in cultured adipocytes, Map4k4 appears not to be involved in the IGF-mediated ERK1/2 signaling axis and the IGF-mediated Akt signaling axis in C2C12 myoblasts. Furthermore, Map4k4 does not affect endogenous Akt signaling or mTOR activity during C2C12 myogenic differentiation. The results presented here not only identify Map4k4 as a novel suppressor of skeletal muscle differentiation, but also add to our knowledge of Map4k4 action on multiple signaling pathways in muscle cells during skeletal myogenesis. The effects that Map4k4 exerts on myoblast differentiation, fusion and Myf5 expression implicate Map4k4 as a potential drug target for muscle mass growth, skeletal muscle regeneration and muscular dystrophy

NUMERICAL STUDY FOR SEAMLESS CLINICAL TRIALS WITH COVARIATE ADAPTIVE RANDOMIZATION

One important goal of the pharmaceutical industry is to evaluate new therapies in a time-sensitive and cost-effective manner without undermining the integrity and validity of clinical trials. Adaptive seamless phase II/III designs (ASD) have gained popularity for accelerating the drug development process and reducing cost. Covariate adaptive randomization (CAR) is the most popular design in randomized controlled trials to ensure valid treatment comparisons by balancing the prognostic characteristics of patients among treatment groups. Although adaptive seamless clinical trials with CAR have been implemented in practice1, the theoretical understanding of such designs is limited. In addition, current approaches to control the Type 1 error rate in seamless trials are based on theories for complete randomization, which may be invalid under CAR and lead to a Type 1 error rate that deviates from the nominal level. Recently, Ma and Zhu (2019, unpublished) established the theoretical foundation for the adaptive seamless phase II/III trial with CAR and proposed a hypothesis testing approach to control the Type 1 error rate in such trials. In the current research, numerical studies were conducted to investigate the feasibility and advantages of the proposed approach in the seamless design with stratified permutated block (SPB) randomization. The simulation results revealed that the newly developed method well controlled the Type 1 error rate around the nominal level, improved the statistical power compared to the standard two sample t-test and increased the number of replications that the best treatment is selected for Stage II of the seamless trial under the SPB design compared to the complete randomization, which could promote its application in practice

Flow Field in a Novel Short Residence Time Gas-solid Separator

The gas flow field in a short residence time separator was investigated. The tangential velocity in the separator housing increases with increasing angle to the positive x axis, and decreases with increasing radial position. A swirl of opposite direction to the main current in the separator housing occurs in the gas outlet

Intrinsic and Extrinsic Connections of Tet3 Dioxygenase with CXXC Zinc Finger Modules.

Tet proteins are emerging as major epigenetic modulators of cell fate and plasticity. However, little is known about how Tet proteins are targeted to selected genomic loci in distinct biological contexts. Previously, a CXXC-type zinc finger domain in Tet1 was shown to bind CpG-rich DNA sequences. Interestingly, in human and mouse the Tet2 and Tet3 genes are adjacent to Cxxc4 and Cxxc10-1, respectively. The CXXC domains encoded by these loci, together with those in Tet1 and Cxxc5, identify a distinct homology group within the CXXC domain family. Here we provide evidence for alternative mouse Tet3 transcripts including the Cxxc10-1 sequence (Tet3(CXXC)) and for an interaction between Tet3 and Cxxc4. In vitro Cxxc4 and the isolated CXXC domains of Tet1 and Tet3(CXXC) bind DNA substrates with similar preference towards the modification state of cytosine at a single CpG site. In vivo Tet1 and Tet3 isoforms with and without CXXC domain hydroxylate genomic 5-methylcytosine with similar activity. Relative transcript levels suggest that distinct ratios of Tet3(CXXC) isoforms and Tet3-Cxxc4 complex may be present in adult tissues. Our data suggest that variable association with CXXC modules may contribute to context specific functions of Tet proteins

Are the Causes of Financial Crisis 2007-2009 Also the Determinants of Bank Performances During the Crisis: Empirical Evidence from US banks

abstract The aim of this paper is to investigate the factors influence bank industry performance. Firstly we listed the causes of financial crisis which was unbelievably virulent to the bank industry and the global economy. Secondly, the bank-specific and macro-economic determinants on bank profitability is examined using the system GMM technique to a unbalance data of US banks in New York, Chicago, Los Angeles, Philadelphia and Houston from 2005 to 2011 covered the financial crisis period. By combining the causes of financial crisis and determinants of banking profitability we find that regulations and improvement in risk estimating are more urgent and efficient than other restrictions. There is a trade-off between bank profitability and expansionary policy. We also find that endogenous money supply as well as foreign cash flows should always be monitored

Enhanced Multimodal Representation Learning with Cross-modal KD

This paper explores the tasks of leveraging auxiliary modalities which are only available at training to enhance multimodal representation learning through cross-modal Knowledge Distillation (KD). The widely adopted mutual information maximization-based objective leads to a short-cut solution of the weak teacher, i.e., achieving the maximum mutual information by simply making the teacher model as weak as the student model. To prevent such a weak solution, we introduce an additional objective term, i.e., the mutual information between the teacher and the auxiliary modality model. Besides, to narrow down the information gap between the student and teacher, we further propose to minimize the conditional entropy of the teacher given the student. Novel training schemes based on contrastive learning and adversarial learning are designed to optimize the mutual information and the conditional entropy, respectively. Experimental results on three popular multimodal benchmark datasets have shown that the proposed method outperforms a range of state-of-the-art approaches for video recognition, video retrieval and emotion classification.Comment: Accepted by CVPR202

Copper-related genes predict prognosis and characteristics of breast cancer

BackgroundThe role of copper in cancer treatment is multifaceted, with copper homeostasis-related genes associated with both breast cancer prognosis and chemotherapy resistance. Interestingly, both elimination and overload of copper have been reported to have therapeutic potential in cancer treatment. Despite these findings, the exact relationship between copper homeostasis and cancer development remains unclear, and further investigation is needed to clarify this complexity.MethodsThe pan-cancer gene expression and immune infiltration analysis were performed using the Cancer Genome Atlas Program (TCGA) dataset. The R software packages were employed to analyze the expression and mutation status of breast cancer samples. After constructing a prognosis model to separate breast cancer samples by LASSO-Cox regression, we examined the immune statement, survival status, drug sensitivity and metabolic characteristics of the high- and low-copper related genes scoring groups. We also studied the expression of the constructed genes using the human protein atlas database and analyzed their related pathways. Finally, copper staining was performed with the clinical sample to investigate the distribution of copper in breast cancer tissue and paracancerous tissue.ResultsPan-cancer analysis showed that copper-related genes are associated with breast cancer, and the immune infiltration profile of breast cancer samples is significantly different from that of other cancers. The essential copper-related genes of LASSO-Cox regression were ATP7B (ATPase Copper Transporting Beta) and DLAT (Dihydrolipoamide S-Acetyltransferase), whose associated genes were enriched in the cell cycle pathway. The low-copper related genes scoring group presented higher levels of immune activation, better probabilities of survival, enrichment in pathways related to pyruvate metabolism and apoptosis, and higher sensitivity to chemotherapy drugs. Immunohistochemistry staining showed high protein expression of ATP7B and DLAT in breast cancer samples. The copper staining showed copper distribution in breast cancer tissue.ConclusionThis study displayed the potential impacts of copper-related genes on the overall survival, immune infiltration, drug sensitivity and metabolic profile of breast cancer, which could predict patients’ survival and tumor statement. These findings may serve to support future research efforts aiming at improving the management of breast cancer