ACTIVATION OF FUNGAL SILENT BIOSYTHETIC PATHWAYS BY EPIGENETIC MODIFICATION

Natural products have played an important role as drug leads for different diseases. They provide unique structural cores with diverse biological activities. Because of the overuse of antibiotics many pathogens have developed antibiotic-resistance; there is an urgent and continuing need for new antibiotics.Fungi are a great source for new natural products with diverse biological activities; fungal genomic sequence data have shown that there are more secondary metabolite pathways than known metabolites. To obtain new natural products, an efficient way is needed to access these silent biosynthetic pathways (SBPs). Currently, different strategies have been used to access silent biosynthetic pathways including culture dependent methods like One Strain Many Compound (OSMAC) and co-culture, and genomic-based methods including heterologous expression and promoter activation. All of the above methods have their limitations, which prohibit their broad usage. In our group we have proposed a simple and feasible method for this purpose. Epigenetic regulation is a process commonly used by fungi to regulate biosynthesis. Epigenetic processes may silence/downregulate some secondary metabolite biosynthetic pathways. Small molecular epigenetic modifiers can inhibit epigenetic targets and upregulate gene expression. In this dissertation I have applied this strategy on two fungi and demonstrated that some secondary metabolite pathways can be activated/upregulated by epigenetic modifiers. Chapter 3 and chapter 4 will focus on the description of using small molecules epigenetic modifier (5-azacytidine) to access SBPs. Chapter 3 reports a significant change in the secondary metabolites excreted by an Atlantic-forest-soil-derived Penicillium citreonigrum, which is a rich source of secondary metabolites. Two new metabolites, atlantinones A and B accompanied by eight known compounds were isolated from the guttates. Chapter 4 describes the application of different culture methods let to the production of different secondary metabolites. Waikialoids A and B were isolated from static culture whereas asperonol A and B were from shaking culture. Chapter 5 is different from above chapters and it mainly focuses on the hybrid NRPS-PKS gene coded metabolites, mutanobactin B-D, which are the signal regulators with other microorganisms

Behind the Great Firewall: The Internet and Democratization in China.

The Internet has changed China profoundly. For the government, the Internet offers prospects to develop economics, education, and technology. For the public, the Internet provides unprecedented opportunities for the free flow of information and communication. Many believe that the Internet will ultimately bring democracy to China, one of the few Communist countries remaining in the world. Relying on multiple methods, including secondary analysis, survey, and in-depth interviews, this study is one of the first attempts to systematically understand how the Internet has been adopted in China, on both provincial and individual levels; and more importantly, how Internet use is associated with people’s real world political lives. Ultimately, this research tries to understand if the Internet could bring a fundamental change in political system to China, and if so, how and when. This research concludes that the Internet is unlikely to offer democratic hope for China, at least not in the near future. Since the Internet is not developed universally, and only a small portion of users are employing it for political activities due to individual characteristics and people’s perceptions of Internet censorship, the Internet’s mobilizing effects are rather constrained. Moreover, due to the rising nationalistic sentiments, the Chinese public were found to be willing to participate in government supported political activity and avoid protests. Nevertheless, the association between nationalism and political participation became less clear when political Internet use increased.Ph.D.CommunicationUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64681/1/wangx_1.pd

Controller Stability and Low-frequency Interaction Analysis of Railway Train-Network Systems

In electrified railways, low-frequency oscillations (LFO) are commonly observed as a result of the widespread implementation of electric trains incorporating power electronic converters. While the impedance method has been employed in current stability studies for train-network systems, there is a requirement to extend stability modeling and analysis studies for the train-network system considering multiple trains having different control strategies. Hence, this paper establishes a unified impedance model in the dq-frame for the aforementioned system. Subsequently, an improved stability criterion, namly the dominant eigenvalue frequency response criterion (DEFRC), is proposed to assess system stability and unveil the mechanism of LFO. Furthermore, the interaction between different trains is clarified by analysis and case studies. Finally, the theoretical analysis is verified for accuracy based on time domain simulations

Siglec15 is a prognostic indicator and a potential tumor-related macrophage regulator that is involved in the suppressive immunomicroenvironment in gliomas

BackgroundSiglec15 is rising as a promising immunotherapeutic target in bladder, breast, gastric, and pancreatic cancers. The aim of the present study is to explore the prognostic value and immunotherapeutic possibilities of Siglec15 in gliomas using bioinformatics and clinicopathological methods.MethodsThe bioinformatics approach was used to examine Siglec15 mRNA expression in gliomas based on TCGA, CGGA, and GEO datasets. Then, the predictive value of Siglec15 expression on progression-free survival time (PFST) and overall survival time (OST) in glioma patients was comprehensively described.The TCGA database was screened for differentially expressed genes (DEGs) between the high and low Siglec15 expression groups, and enrichment analysis of the DEGs was performed. The Siglec15 protein expression and its prognostic impact in 92 glioma samples were explored using immunohistochemistry Next, the relationships between Siglec15 expression and infiltrating immune cells, immune regulators and multiple immune checkpoints were analysed.ResultsBioinformatics analyses showed that high Siglec15 levels predicted poor clinical prognosis and adverse recurrence time in glioma patients. In the immunohistochemical study serving as a validation set, Siglec15 protein overexpression was found in 33.3% (10/30) of WHO grade II, 56% (14/25) of WHO grade III, and 70.3% (26/37) of WHO grade IV gliomas respectively. Siglec15 protein overexpression was also found to be an independent prognostic indicator detrimental to the PFST and OST of glioma patients. Enrichment analysis showed that the DEGs were mainly involved in pathways associated with immune function, including leukocyte transendothelial migration, focal adhesion, ECM receptor interaction, and T-cell receptor signaling pathways. In addition, high Siglec15 expression was related to M2 tumor-associated macrophages (TAMs), N2 tumor-infiltrating neutrophils, suppressive tumor immune microenvironment, and multiple immune checkpoint molecules. Immunofluorescence analysis confirmed the colocalization of Siglec15 and CD163 on TAMs.ConclusionSiglec15 overexpression is common in gliomas and predicts an adverse recurrence time and overall survival time. Siglec15 is a potential target for immunotherapy and a potential TAMs regulator that is involved in the suppressed immunomicroenvironment in gliomas

HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation

SummaryThe terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion. We show that a histone deacetylase 3 (Hdac3)-mediated epigenetic pathway is critical for the proper remodeling and expansion of the distal lung saccules into primitive alveoli. Loss of Hdac3 in the developing lung epithelium leads to a reduction of alveolar type 1 cell spreading and a disruption of lung sacculation. Hdac3 represses miR-17-92 expression, a microRNA cluster that regulates transforming growth factor β (TGF-β) signaling. De-repression of miR-17-92 in Hdac3-deficient lung epithelium results in decreased TGF-β signaling activity. Importantly, inhibition of TGF-β signaling and overexpression of miR-17-92 can phenocopy the defects observed in Hdac3 null lungs. Conversely, loss of miR-17-92 expression rescues many of the defects caused by loss of Hdac3 in the lung. These studies reveal an intricate epigenetic pathway where Hdac3 is required to repress miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation

Exploring the experience of meaning-centered group psychotherapy among Chinese cancer patients during active treatment: a descriptive qualitative study

ObjectiveMeaninglessness poses a significant psychological challenge for cancer patients, negatively affecting their quality of life and increasing the risk of suicide. Meaning-Centered Group Therapy (MCGP) is an intervention designed specifically to enhance the meaning of life of cancer patients. Extensive research has documented its effectiveness across various cultures and populations. However, limited research has been conducted on the subjective experiences and perspectives of participants engaged in MCGP. Thus, the purpose of this study was to employ a qualitative design to explore the experiences and viewpoints of Chinese cancer patients who have undergone MCGP.MethodsWithin a two-week timeframe following the conclusion of MCGP, semi-structured interviews were administered to twenty-one participants who had engaged in the therapy. The interview data were transcribed and subjected to thematic analysis.ResultsFour main themes were identified: (a) Self-perceived personal change, (b) Overall experience of group therapy, (c) Barriers to participation of MCGP, and (d) Suggestions for future interventions.ConclusionDespite the barriers to participation in the MCGP process, the overall experience for Chinese cancer patients undergoing active treatment is valuable and positive, providing multiple benefits. Future studies could explore the adaptation of MCGP to a broader range of cancer populations and diverse study populations