Involvement of CDP/Cux in the Regulation of Histone H4 Gene Expression, Proliferation and Differentiation: a Dissertation

Proliferation and differentiation are essential processes for the growth and development of higher eukaryotic organisms. Regulation of gene expression is essential for control of cell division and differentiation. Normal eukaryotic cells have a limited proliferative capacity, and ultimately undergo cellular senescence and apoptosis. Terminal differentiation of cells is associated with loss of proliferative capacity and acquisition of specialized functions. Proliferation and differentiation are processes required for the creation and maintenance of diverse tissues both during embryonic development and postnatal life. The cell cycle is the process by which cells reproduce, and requires duplication and segregation of hereditary material. Loss of cell cycle control leads to genetic instability and cancer. Expression of replication-dependent histone genes is tightly coupled to DNA synthesis, thus making histone genes a good model for studying cell cycle regulation. The HiNF-D complex interacts with all five classes (H1, H2A, H2B, H3 and H4) of histone genes in a cell cycle-dependent manner. The CCAAT displacement protein (CDP)/Cux and the tumor suppressor pRB are key components of the HiNF-D complex. However, the molecular interactions that enable CDP/Cux and pRB to form a complex and thus convey cell growth regulatory information onto histone gene promoters are poorly understood. Transient transfection assays show that CDP/Cux represses the histone H4 promoter and that the pRB large pocket domain functions with CDP/Cux as a co-repressor. Direct interaction between CDP/Cux C-terminus and the pRB pocket domain was observed in GST pull-down assays. Furthermore, co-immunoprecipitation assays and immunofluorescence microscopy established that CDP/Cux and pRB form complexes in vivo and associate in situ. pRB interaction and co-repression with CDP/Cux is independent of pRB phosphosphorylation sites, as revealed by GST pull-down assays and transient transfection assays using a series of pRB mutant proteins. Thus, several converging lines of evidence indicate that complexes between CDP/Cux and pRB repress cell cycle-regulated histone gene promoters. CDP/Cux is regulated by phosphorylation and acetylation at the C-terminus, which contains two repressor domains and interacts with histone deacetylase HDAC1. In vivo function of the CDP/Cux C-terminus in development and gene regulation was assessed in genetically targeted mice (Cutl1tm2Ejn, referred to as Cutl1ΔC). The mice express a mutant CDP/Cux protein with a deletion of the C-terminus including the homeodomain. Indirect immunofluorescence microscopy showed that the mutant protein exhibited significantly reduced nuclear localization in comparison to the wildtype protein. Consistent with these data, DNA binding activity of HiNF-D was lost in nuclear extracts derived from mouse embryonic fibroblasts (MEFs) or adult tissues of homozygous mutant (Cutl1 ΔC -/-) mice, indicating the functional loss of CDP/Cux in the nucleus. No significant difference in growth characteristics or total histone H4 mRNA levels was observed between wildtype and Cutl1 ΔC -/- MEFs in culture. However, the histone H4.1 (murine FO108) gene containing CDP/Cux binding sites have reduced expression levels in homozygous mutant MEFs. Stringent control of growth and differentiation appears to be compromised in vivo. Homozygous mutant mice exhibit stunted growth (20-50% weight reduction), a high postnatal death rate of 60-70%, sparse abnormal coat hair and severely reduced fertility. Hair follicle deformities and severely diminished fertility in Cutl1 ΔC -/- mice suggest that CDP/Cux is required for normal development of dermal tissues and reproductive functions. Together the data presented in this dissertation provide new insight into the in vivo functions of CDP/Cux in the regulation of histone gene expression, growth control and differentiation

When is a firm's information asymmetry priced? The role of institutional investors

This study reexamines the competing claims that probability of informed trading (PIN) is priced in the cross-section of stock returns while adjusted PIN (AdjPIN), the component of PIN related to information asymmetry, is not. We find that behind these seemingly contradicting conclusions is the role of institutional investors, and the pricing of PIN and AdjPIN depends on institutional ownership. Only for those stocks with low institutional ownership are both PIN and AdjPIN priced. Our findings imply that investors require compensation for information risk only from stocks with low institutional ownership

How do foreign institutional investors enhance firm innovation?

We examine the effect of foreign institutional investors on firm innovation. Using firm-level data across 26 non-U.S. economies between 2000 and 2010, we show that foreign institutional ownership has a positive, causal effect on firm innovation. We further explore three possible underlying mechanisms through which foreign institutions affect firm innovation: Foreign institutions act as active monitors, provide insurance for firm managers against innovation failures, and promote knowledge spillovers from high-innovation economies. Our article sheds new light on the real effects of foreign institutions on firm innovation

VLSP SHARED TASK: SENTIMENT ANALYSIS

Sentiment analysis is a natural language processing (NLP) task of identifying orextracting the sentiment content of a text unit. This task has become an active research topic since the early 2000s. During the two last editions of the VLSP workshop series, the shared task on Sentiment Analysis (SA) for Vietnamese has been organized in order to provide an objective evaluation measurement about the performance (quality) of sentiment analysis tools, and encouragethe development of Vietnamese sentiment analysis systems, as well as to provide benchmark datasets for this task. The rst campaign in 2016 only focused on the sentiment polarity classication, with a dataset containing reviews of electronic products. The second campaign in 2018 addressed the problem of Aspect Based Sentiment Analysis (ABSA) for Vietnamese, by providing two datasets containing reviews in restaurant and hotel domains. These data are accessible for research purpose via the VLSP website vlsp.org.vn/resources. This paper describes the built datasets as well as the evaluation results of the systems participating to these campaigns

The PLATO Dome A Site-Testing Observatory : instrumentation and first results

The PLATeau Observatory (PLATO) is an automated self-powered astrophysical observatory that was deployed to Dome A, the highest point on the Antarctic plateau, in 2008 January. PLATO consists of a suite of site-testing instruments designed to quantify the benefits of the Dome A site for astronomy, and science instruments designed to take advantage of the unique observing conditions. Instruments include CSTAR, an array of optical telescopes for transient astronomy; Gattini, an instrument to measure the optical sky brightness and cloud cover statistics; DASLE, an experiment to measure the statistics of the meteorological conditions within the near-surface layer; Pre-HEAT, a submillimeter tipping radiometer measuring the atmospheric transmission and water vapor content and performing spectral line imaging of the Galactic plane; and Snodar, an acoustic radar designed to measure turbulence within the near-surface layer. PLATO has run completely unattended and collected data throughout the winter 2008 season. Here we present a detailed description of the PLATO instrument suite and preliminary results obtained from the first season of operation

Cell responses and hemocompatibility of g-HA/PLA composites

The objective of this study was to investigate the hemocompatibility and cell responses to some novel poly(L-lactide) (PLA) composites containing surface modified hydroxyapatite particles for potential applications as a bone substitute material. The surface of hydroxyapatite (HA) particles was first grafted with L-lactic acid oligomers to form grafted HA (g-HA) particles. The g-HA particles were further blended with PLA to prepare g-HA/PLA composites. Our previous study has shown significant improvement in tensile properties of these materials due to the enhanced interfacial adhesion between the polymer matrix and HA particles. To further investigate the potential applications of these composites in bone repair and other orthopedic surgeries, a series of in vitro and in vivo experiments were conducted to examine the cell responses and hemocompatibility of the materials. In vitro experiments showed that the g-HA/PLA composites were well tolerated by the L-929 cells. Hemolysis of the composites was lower than that of pure PLA. Subcutaneous implantation demonstrated that the g-HA/PLA composites were more favorable than the control materials for soft tissue responses. The results suggested that the g-HA/PLA composites are promising and safe materials with potential applications in tissue engineering

Assessment of the Effectiveness of Ich Tam Khang as a Supportive Therapy for Chronic Heart Failure

Background: Heart failure is a chronic disease needing lifelong management. Despite the advances that have been made in the treatment of the disease, both the longevity and quality of life for those with chronic heart failure remain impaired. A more effective therapeutic approach with less negative side effects is still needed. In this study, we evaluate Ich Tam Khang (ITK), the poly-ingredient herbal and nutritional preparation with multiple physiological actions, as a supportive therapy for patients with chronic heart failure.Aims of Study: To evaluate the effectiveness and safety of Ich Tam Khang as an adjunctive treatment of chronic heart failure.Methods: A total of 60 patients with chronic congestive heart failure were enrolled in this open label, cross-sectional and prospective study. All patients were treated with a conventional regimen (digoxin, diuretics, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), beta blockers) for at least 4 weeks before being divided into two equal groups. In the treated patients with ITK, patients received conventional therapy plus 4 tablets ITK per day added in two divided doses. In the control patients, all patients kept the same conventional regimen without ITK. All patients were followed up for 3 months for clinical and para-clinical outcomes.Result: The symptoms of heart failure (dyspnea, palpitation, peripheral edema, neck vein distention, heptojugular reflex) decreased. Heart rate and blood pressure stabilized during treatment in the treated patients with ITK. Additionally, total cholesterol and HDL-cholesterol normalized in the patients treated with ITK. Most of echocardiography parameters in the ITK treated patients were superior to the control patients. ITK is safe and it has no side effects.Conclusion: ITK as a combination of herbal and nutritional preparation is effective in reducing heart failure symptoms, improving patient's quality of life for the patients with decompensated heart failure and reducing total cholesterol and LDL-C