Developing Primary Propulsion for the Ares I Crew Launch Vehicle and Ares V Cargo Launch Vehicle

In accordance with the U.S. Vision for Space Exploration, NASA has been tasked to send human beings to the moon, Mars, and beyond. The first stage of NASA's new Ares I crew launch vehicle (Figure 1), which will loft the Orion crew exploration vehicle into low-Earth orbit early next decade, will consist of a Space Shuttle-derived five-segment Reusable Solid Rocket Booster (RSRB); a pair of similar RSRBs also will be used on the Ares V cargo launch vehicle's core stage propulsion system. This paper will discuss the basis for choosing this particular propulsion system; describe the activities the Exploration Launch Projects (ELP) Office is engaged in at present to develop the first stage; and offer a preview of future development activities related to the first Ares l integrated test flight, which is planned for 2009

Shared reading of children's interactive picture books

We report on a study of children and parents shared reading of interactive printed books. We investigated the differences between books with interactive features and books with expressive typography in order to evaluate which features within a book encouraged interaction between the reading participants and the book. 11 parent and child groups took part in the study that involved three observed reading sessions. From our observations we offer suggestions for the development of books and eBooks to encourage shared reading practices

U.S. Commission on Immigration Reform

The U.S. Commission on Immigration Reform was created by Congress to assess U.S. immigration policy and make recommendations regarding its implementation and effects. Mandated in the Immigration Act of 1990 to submit an interim report in 1994 and a final report in 1997, the Commission has undertaken public hearings, fact-finding missions, and expert consultations to identify the major immigration-related issues facing the United States today.LBJ School of Public Affair

Recognizing and Overcoming Difficult Site Conditions for Afforestation of Bottomland Hardwoods

In the last decade, about 370,000 acres (150,000 ha) of economically marginalfarmland in the Lower Mississippi Alluvial Valley (LMAV) have been restored tobottomland hardwood forests (Stanturf and others 1998, King and Keeland 1999,Schoenholtz and others 2001). Planting of this considerable acreage is due to several federal programs, such as the Wetlands Reserve Program (WRP), that assist landowners by financing afforestation (Figure 1). Unfortunately, these operational plantings have not performed as well as smaller plantings or research plots (Stanturf and others 2001a). For example, a recent survey of WRP plantings in westcentral Mississippi revealed that more than 90 percent of the sites failed to meet the criteria of 100 woody stems per acre (247 stems per ha) three years after planting or direct seeding. While planting 1-0 bareroot seedlings of oak was more successful than direct-seeding acorns, only 23percent of the land planted with seedlings met the criteria (C.J. Schweitzer unpublished data). Planting and direct seeding oak (Quercus spp.) on public land in the same area has been more successful. Meanwhile, Allen (1990) found 70 percent of the planted bottomland hardwood stands on the national wildlife refuges he evaluated had more than 200 trees per acre (494 stems per ha).We believe that the recurring problems in operational plantings on privatelands are due in part to the failure of planters to recognize adverse site conditions and their failure to use appropriate methods for overcoming site limitations. Our objectives in this paper are to synthesize research and experience into guidelines for recognizing adverse site conditions due to hydroperiod, soil, competing vegetation, and herbivory. We describe techniques for overcoming these conditions and suggest promising research areas

YB-1 transcription factor promotes Sorafenib resistance in Liver Cancer

Background: Hepatocellular carcinoma (HCC) is a primary malignant liver tumor that commonly occurs as a progression of chronic liver inflammation. Sorafenib is the standard first-line systemic drug for advanced HCC, but the acquired resistance to sorafenib results in limited benefits. The mechanism underlying sorafenib resistance in HCC remains unclear. Recently, we have identified a multifunctional oncoprotein Y-box binding protein-1 (YB-1) that dysregulates a wide range of genes involved in drug resistance in other cancers and is responsible for increasing the IC-50 of sorafenib in HCC cell lines. In this study we will analyze the signaling pathways and genes regulated by YB-1, that is responsible for increasing sorafenib resistant in liver cancer cells. Methods: HCC cell lines SK-Hep-1, C3A, HepG2 and Hep-3B were treated with Sorafenib and the IC-50 was calculated using MTT assay. RNA and protein of YB-1 was analyzed using RT-PCR and western blot respectively. Lentiviral based overexpression and knockdown of YB1 was performed in these cell lines and sorafenib IC50 were calculated to verify its role in Sorafenib resistance. Development of sorafenib resistant cell line is in progress. Results: IC-50 values calculated from MTT assays of the HCC cell lines were compared with the YB-1 protein expression in four liver cancer cell lines. Knockdown of YB-1 re-sensitized cell lines to Sorafenib. We have developed Sorafenib resistant cell lines to further study the mechanism of YB-1 mediated drug resistance. Conclusion: This study will establish oncogenic YB-1 protein as an effective therapeutic target to overcome sorafenib resistance in liver cancer

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor

The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the ‘DFG-out’ conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction