Characterization of ALDH1A1 as a novel tumorigenic target mediating TAZ-induced lung tumorigenesis and stem cell phenotypes

Recent studies suggest that lung cancer stem cells (CSCs) may play major roles in lung cancer development, metastasis and drug resistance. Therefore, identification of lung CSC drivers may provide promising targets for lung cancer. TAZ (transcriptional co-activator with PDZ-binding motif) is a transcriptional co-activator and key downstream effector of the Hippo pathway, which plays critical roles in various biological processes. TAZ has been shown to be overexpressed in non-small cell lung cancer (NSCLC) and involved in tumorigenicity of lung epithelial cells. However, whether TAZ is a driver for lung CSCs and tumor formation in vivo is unknown. In addition, the molecular mechanism underlying TAZ-induced lung tumorigenesis remains to be determined. In this study, we provided evidence that constitutively active TAZ (TAZ-S89A) is a driver for lung tumorigenesis in vivo in mice and formation of lung CSC. Oncogenes upregulated in TAZ-overexpressing cells were identified with further validation. The most dramatically activated gene, Aldh1a1 (Aldehyde dehydrogenase 1 family member a1), a well-established CSC marker, showed that TAZ induces Aldh1a1 transcription by activating its promoter activity through interaction with the transcription factor TEA domain (TEAD) family member. Most significantly, inhibition of ALDH1A1 with its inhibitor A37 or CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene knockout in lung cancer cells suppressed lung tumorigenic and CSC phenotypes in vitro, and tumor formation in mice in vivo. In conclusion, this study identified TAZ as a novel inducer of lung CSCs and the first transcriptional activator of the stem cell marker ALDH1A1. Most significantly, we identified ALDH1A1 as a critical meditator of TAZ-induced tumorigenic and CSC phenotypes in lung cancer. Our studies provided preclinical data for targeting of TAZ-TEAD-ALDH1A1 signaling to inhibit CSC-induced lung tumorigenesis and drug resistance in the future.

SINGLE STAGE LED DRIVER TECHNOLOGY WITH LOW FREQUENCY RIPPLE CANCELLATION

Because of high efficacy, long lifespan, and environment-friendly operation, LED lighting devices become more and more popular in every part of our life, such as ornament/interior lighting, outdoor lightings and flood lighting. The LED driver is the most critical part of the LED lighting fixture. It heavily affects the purchasing cost, operation cost as well as the light quality. Design a high efficiency, low component cost and flicker-free LED driver is the goal. The conventional single-stage LED driver can achieve low cost and high efficiency. However, it inevitably produces significant twice-line-frequency lighting flicker, which adversely affects our health. The conventional two-stage LED driver can achieve flicker-free LED driving at the expenses of significantly adding component cost, design complexity and low the efficiency. The basic ripple cancellation LED driving method has been proposed in chapter three. It achieves a high efficiency and a low component cost as the single-stage LED driver while also obtaining flicker-free LED driving performance. The basic ripple cancellation LED driver is the foundation of the entire thesis. As the research evolving, another two ripple cancellation LED drivers has been developed to improve different aspects of the basic ripple cancellation LED driver design. The primary side controlled ripple cancellation LED driver has been proposed in chapter four to further reduce cost on the control circuit. It eliminates secondary side compensation circuit and an opto-coupler in design while at the same time maintaining flicker-free LED driving. A potential integrated primary side controller can be designed based on the proposed LED driving method. The energy channeling ripple cancellation LED driver has been proposed in chapter five to further reduce cost on the power stage circuit. In previous two ripple cancellation LED drivers, an additional DC-DC converter is needed to achieve ripple cancellation. A power transistor has been used in the energy channeling ripple cancellation LED driving design to successfully replace a separate DC-DC converter and therefore achieved lower cost. The detailed analysis supports the theory of the proposed ripple cancellation LED drivers. Simulation and experiment have also been included to verify the proposed ripple cancellation LED drivers.

Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Historical comparisons reveal multiple drivers of decadal change of an ecosystem engineer at the range edge

Biogenic reefs are important for habitat provision and coastal protection. Long-term datasets on the distribution and abundance of Sabellaria alveolata (L.) are available from Britain. The aim of this study was to combine historical records and contemporary data to (1) describe spatiotemporal variation in winter temperatures, (2) document short-term and long-term changes in the distribution and abundance of S. alveolata and discuss these changes in relation to extreme weather events and recent warming, and (3) assess the potential for artificial coastal defense structures to function as habitat for S. alveolata. A semi-quantitative abundance scale (ACFOR) was used to compare broadscale, long-term and interannual abundance of S. alveolata near its range edge in NW Britain. S. alveolata disappeared from the North Wales and Wirral coastlines where it had been abundant prior to the cold winter of 1962/1963. Population declines were also observed following the recent cold winters of 2009/2010 and 2010/2011. Extensive surveys in 2004 and 2012 revealed that S. alveolata had recolonized locations from which it had previously disappeared. Furthermore, it had increased in abundance at many locations, possibly in response to recent warming. S. alveolata was recorded on the majority of artificial coastal defense structures surveyed, suggesting that the proliferation of artificial coastal defense structures along this stretch of coastline may have enabled S. alveolata to spread across stretches of unsuitable natural habitat. Long-term and broadscale contextual monitoring is essential for monitoring responses of organisms to climate change. Historical data and gray literature can be invaluable sources of information. Our results support the theory that Lusitanian species are responding positively to climate warming but also that short-term extreme weather events can have potentially devastating widespread and lasting effects on organisms. Furthermore, the proliferation of coastal defense structures has implications for phylogeography, population genetics, and connectivity of coastal populations.

Historical comparisons reveal multiple drivers of decadal change of an ecosystem engineer at the range edge

Biogenic reefs are important for habitat provision and coastal protection. Long-term datasets on the distribution and abundance of Sabellaria alveolata (L.) are available from Britain. The aim of this study was to combine historical records and contemporary data to (1) describe spatiotemporal variation in winter temperatures, (2) document short-term and long-term changes in the distribution and abundance of S. alveolata and discuss these changes in relation to extreme weather events and recent warming, and (3) assess the potential for artificial coastal defense structures to function as habitat for S. alveolata. A semi-quantitative abundance scale (ACFOR) was used to compare broadscale, long-term and interannual abundance of S. alveolata near its range edge in NW Britain. S. alveolata disappeared from the North Wales and Wirral coastlines where it had been abundant prior to the cold winter of 1962/1963. Population declines were also observed following the recent cold winters of 2009/2010 and 2010/2011. Extensive surveys in 2004 and 2012 revealed that S. alveolata had recolonized locations from which it had previously disappeared. Furthermore, it had increased in abundance at many locations, possibly in response to recent warming. S. alveolata was recorded on the majority of artificial coastal defense structures surveyed, suggesting that the proliferation of artificial coastal defense structures along this stretch of coastline may have enabled S. alveolata to spread across stretches of unsuitable natural habitat. Long-term and broadscale contextual monitoring is essential for monitoring responses of organisms to climate change. Historical data and gray literature can be invaluable sources of information. Our results support the theory that Lusitanian species are responding positively to climate warming but also that short-term extreme weather events can have potentially devastating widespread and lasting effects on organisms. Furthermore, the proliferation of coastal defense structures has implications for phylogeography, population genetics, and connectivity of coastal populations.

Mathematical Modeling to Assess the Drivers of the Recent Emergence of Typhoid Fever in Blantyre, Malawi

BACKGROUND: Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains.

METHODS: To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R0) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype.

RESULTS: Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data.

CONCLUSIONS: Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa.

Northern Ireland Policing Board Confidence in Policing Research: Key Drivers of Confidence

In January 2014, the Northern Ireland Policing Board (NIPB) commissioned the University of Ulster to conduct research into public confidence in policing to help inform the work of the Board and its oversight of police service delivery. More specifically, the research team were tasked with exploring ‘the key drivers of confidence in Northern Ireland’. To date, the subject of ‘confidence in policing’ within a Northern Ireland context has been relatively under researched, both in academic and policy terms. Thus, the present research is the first empirical research to be produced in the country to empirically assess confidence in policing from a cross section of society – including the key dynamics and drivers that underpin police confidence at a community level.

The report begins with a comprehensive review of academic literature, policy documents and contemporary events related to confidence in policing. The research then provides an overview of the methodology used to undertake the research, with the remainder of the report comprised of the findings from the survey. The report concludes with an overview of the central findings along with a series of recommendations.

Licensed Iowa Drivers by County 2007-2015, January 29, 2016

Licensed Iowa drivers by county spreadsheet.

Iowa Crash History 2001 to 2015: Drivers Distracted by Use of Phone or Other Device, May 11, 2016

Iowa crash history of distracted drivers by use of phone or other devices.

Licensed Iowa Drivers by by Age Group & Sex - 2007 to 2015, January 29, 2016

Licensed Iowa drivers by age ground and sex spreadsheet.

Drivers' Behavior at Railroad Grade Crossings: Before and After Safety Campaign, HR-335, Survey Data Summaries, 1992

Summaries of the data gathered for this project.

An Empirical Analysis of Manufacturing Overhead Cost Drivers

Empirical validity of the claim that overhead costs are driven not by production volume but by transactions resulting from production complexity is examined using data from 32 manufacturing plants from the electronics, machinery, and automobile components industries. Transactions are measured using number of engineering change orders, number of purchasing and production planning personnel, shop- floor area per part, and number of quality control and improvement personnel. Results indicate a strong positive relation between manufacturing overhead costs and both manufacturing transactions and production volume. Most of the variation in overhead costs, however, is explained by measures of manufacturing transactions, not volume.

Road Life Perspectives and Experiences Among Iranian Truck Drivers: a Qualitative Study

Truck drivers are one of the largest occupational groups in Iran. Evidence from previous studies suggests that working and living conditions on the road engender many concerns for truck drivers, and their families and communities. This research aimed to explore the experiences of Iranian truck drivers regarding life on the road. This qualitative study was conducted among Iranian truck drivers working in the inter-state transportation sector. A purposeful sample of 20 truck drivers took part in this research. Data were collected through semi-structured interviews and analyzed based on qualitative content analysis. After analysis of the data, three main themes emerged: "Individual impacts related to the hardships of life on the road life", "Family impacts related to the hardships of road life", and "Having positive attitude towards work and road". These findings represent the dimensions of perspectives in the road-life of truck drivers. Although truck drivers possess positive beliefs about their occupation and life on the road, they and their families face many hardships which should be well understood. They also need support to be better able to solve the road-life concerns they face. This study's findings are useful for occupational programming and in the promotion of health for truck drivers.

Older Adult Injury Risk Assessment in the Driving and Occupational Environments

Thesis (Ph.D.)--University of Washington, 2016-08