The Design, Synthesis, and Investigation into Small Molecule Modulators of the Src Homology 2 Domain-Containing Inositol 5’-Phosphatase (SHIP)

The PI3K pathway is a major cell signaling pathway that influences survival and longevity in eukaryotic cells. Abnormal signaling of this pathway has been implicated in a number of disorders, including Alzheimer\u27s disease and cancer. The PI3K pathway utilizes the inositolphospholipid PI(3,4,5)P3 as a key secondary messenger in the transmission of signals from outside the cell to the nucleus. The SRC Homology 2 containing Inositol 5’-Phosphatase (SHIP) also plays a key role in the PI3K pathway, mediating hydrolysis of the inositol phospholipid PI(3,4,5)P3 to PI(3,4)P2. Early testing has shown modulation of SHIP activity through the use of small molecule modulators is effective at treating certain types of cancer and inflammatory diseases in cell-based assays and in murine xenografts.This report details the investigation into tryptamine-based pan-SHIP1/2 inhibitors, as well as studies into a newly discovered sulfonamide-based SHIP1 selective agonist. Attempts to modulate SHIP activity by means of small molecules led us to develop and synthesize various small molecule tryptamine inhibitors in hopes of increasing the selectivity and potency, as well as probe the structure-activity relationships. The recently uncovered bis-sulfonamide SHIP1 agonist was synthesized for preliminary testing and investigation. Additionally, studies were undertaken to design and synthesis new sulfonamide-based SHIP1 agonists allowing for the development of more potent agonists that are less likely to biodegrade when exposed to CYP enzymes

Dietary Choline and Betaine and Risk of CVD: A Systematic Review and Meta-Analysis of Prospective Studies

Studies implicate choline and betaine metabolite trimethylamine N-oxide (TMAO) in cardiovascular disease (CVD). We conducted a systematic review and random-effects meta-analysis to quantify a summary estimated effect of dietary choline and betaine on hard CVD outcomes (incidence and mortality). Eligible studies were prospective studies in adults with comprehensive diet assessment and follow-up for hard CVD endpoints. We identified six studies that met our criteria, comprising 18,076 incident CVD events, 5343 CVD deaths, and 184,010 total participants. In random effects meta-analysis, incident CVD was not associated with choline (relative risk (RR): 1.00; 95% CI: 0.98, 1.02) or betaine (RR: 0.99; 95% CI: 0.98, 1.01) intake. Results did not vary by study outcome (incident coronary heart disease, stroke, total CVD) and there was no evidence for heterogeneity among studies. Only two studies provided data on phosphatidylcholine and CVD mortality. Random effects meta-analysis did not support an association between choline and CVD mortality (RR: 1.09, 95% CI: 0.89, 1.35), but one study supported a positive association and there was significant heterogeneity (I2 = 84%, p-value < 0.001). Our findings do not support an association between dietary choline/betaine with incident CVD, but call for further research into choline and CVD mortality

Diversification and hybridization in firm knowledge bases in nanotechnologies

The paper investigates the linkages between the characteristics of technologies and the structure of a firms' knowledge base. Nanotechnologies have been defined as converging technologies that operate at the nanoscale, and which require integration to fulfill their economic promises. Based on a worldwide database of nanofirms, the paper analyses the degree of convergence and the convergence mechanisms within firms. It argues that the degree of convergence in a firm's nano-knowledge base is relatively independent from the size of the firm's nano-knowledge base. However, while firms with small nano-knowledge bases tend to exploit convergence in each of their patents/publications, firms with large nano-knowledge bases tend to separate their nano-R&D activities in the different established fields and achieve diversity through the juxtaposition of the output of these independent activitie

Birth room transition support for term and near-term infants : A cochrane overview

This is a protocol for a Cochrane Review (Overview). The objectives are as follows: We will describe and summarise Cochrane Reviews of birth room interventions for term or near-term newborn infants, and assess their methodological quality and the validity of their findings. We will map the evidence from Cochrane Reviews and identify important gaps in the evidence base. We will not compare multiple interventions with the intention of drawing inferences about their comparative effectiveness

Designer Gene Networks: Towards Fundamental Cellular Control

The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics.Comment: 35 pages, 8 figure

Birth room transition support for preterm infants : A cochrane overview

This is a protocol for a Cochrane Review (Overview). The objectives are as follows: We will describe and summarise Cochrane Reviews of birth room interventions for preterm infants, and assess their methodological quality and the validity of their findings.We will map the evidence from Cochrane Reviews and identify important gaps in the evidence base. We will not compare multiple interventions with the intention of drawing inferences about their comparative effectiveness

Teaching presence in computer conferencing learning environments: Effects on interaction, cognition and learning uptake

This exploratory study examined how the level and nature of teaching presence impacted two online forum discussions from three dimensions: participation and interaction, cognitive presence, and knowledge development via assimilating peer messages. Effects on participation and interaction were graphically depicted. Effects on cognitive presence and knowledge construction via assimilating messages were suggested via statistical analysis, followed by qualitative interpretations. Twenty-six tertiary online learners with varied demographic backgrounds participated in the study for 6 weeks. The results showed that the nature of teaching presence in the study, specified to teacher initiation, roles of teaching presence and means of making teaching presence, largely shaped the impact of teaching presence on learning. A higher level of teaching presence was observed to be associated with a lower level of student participation, peer interaction, cognitive presence and learning uptake. Based on the results, implications for integrating and researching teaching presence in computer conferences were provided

Superconductivity in Ropes of Single-Walled Carbon Nanotubes

We report measurements on ropes of Single Walled Carbon Nanotubes (SWNT) in low-resistance contact to non-superconducting (normal) metallic pads, at low voltage and at temperatures down to 70 mK. In one sample, we find a two order of magnitude resistance drop below 0.55 K, which is destroyed by a magnetic field of the order of 1T, or by a d.c. current greater than 2.5 microA. These features strongly suggest the existence of superconductivity in ropes of SWNT.Comment: Accepted for publication in Phys. Rev. Let

Statewide geographic variation in outcomes for adults with acute myeloid leukemia in North Carolina

BACKGROUND: Population-based studies have demonstrated survival disparities related to socioeconomic factors for patients with acute myeloid leukemia (AML). The objective of the current study was to determine whether the local health care infrastructure, represented by Area Health Education Centers (AHEC) region, or treating center experience, represented by National Cancer Institute Comprehensive Cancer Center (NCICCC) designation, were associated with outcomes among patients with AML in North Carolina. METHODS: Patients who were diagnosed with AML from 2003 to 2009 were identified using the University of North Carolina Lineberger Integrated Cancer Information and Surveillance System, a database linking insurance claims to the North Carolina Cancer Registry. A Cox proportional-hazards model was used to explore survival based on AHEC region. A subset of patients who received inpatient chemotherapy was examined to evaluate the impact of treatment at an NCICCC. RESULTS: Nine hundred patients were identified in the study period, 553 of whom received inpatient chemotherapy therapy within 30 days of diagnosis. Almost one-half of these patients (n5294) received chemotherapy at a non-NCICCC. Among the patients who received intensive inpatient therapy, residence in 3 of 9 AHEC regions was associated with a higher risk of mortality (hazard ratio: range, 1.97-4.03; P<.01) at 1 year in multivariate analysis. Treatment at a non-NCICCC was not associated with an increased risk of mortality at 1 year (hazard ratio, 1.25; 95% confidence interval, 0.95-1.65). CONCLUSIONS: Survival among patients with AML in North Carolina varies according to geographic region. Further examination of local practice and referral patterns may inform strategies to improve AML outcomes across the state