Cell Competition During Growth and Regeneration

Tissue growth and regeneration are autonomous, stem-cell-mediated processes in which stem cells within the organ self-renew and differentiate to create new cells, leading to new tissue. The processes of growth and regeneration require communication and interplay between neighboring cells. In particular, cell competition, which is a process in which viable cells are actively eliminated by more competitive cells, has been increasingly implicated to play an important role. Here, we discuss the existing literature regarding the current landscape of cell competition, including classical pathways and models, fitness fingerprint mechanisms, and immune system mechanisms of cell competition. We further discuss the clinical relevance of cell competition in the physiological processes of tissue growth and regeneration, highlighting studies in clinically important disease models, including oncological, neurological, and cardiovascular diseases.

Forecasting and Analyzing Economic Activity with Coincident and Leading Indexes: The Case of Connecticut

We develop coincident and leading employment indexes for the Connecticut economy. Four employment-related variables enter the coincident index while five employment-related variables enter the leading index. The peaks and troughs in the leading index lead the peaks and troughs in the coincident index by an average of 3 and 9 months. Finally, we use the leading index in vector-autoregressive (VAR) and Bayesian vector-autoregressive (BVAR) models to forecast the coincident index, nonfarm employment, and the unemployment rate.

EGFR and Notch signaling pathways are regulated by distinct isoforms of Drosophila cbl

Activation of cell surface receptors transduces extracellular signals into cellular responses such as proliferation, differentiation and survival. However, the appropriate spatial and temporal down-regulation of signaling receptors is essential for normal development and homeostasis. The Cbl family of E3-ubiquitin ligases plays a major role for the ligand-dependent inactivation of growth factor receptors through ubiquitin-mediated endocytosis and lysosomal degradation. Here, we report the D-cbl mutant phenotypes in the Drosophila eye. D-cbl mutants display overgrowth, inhibition of apoptosis, differentiation defects and increased ommatidial spacing. Many of these phenotypes are caused by lack of down-regulation of the Drosophila EGFR signaling. However, not all D-cbl phenotypes can be explained by inappropriate EGFR activity. We found that D-Cbl also negatively regulates Notch activity during eye and wing development. D-cbl produces two isoforms by alternative splicing. Strikingly, the long isoform, D-CblL, preferentially regulates the EGFR, whereas the short isoform, D-CblS, preferentially regulates Notch. Taken together, these data suggest that D-Cbl controls at least two signaling pathways, EGFR and Notch, through production of two alternatively spliced isoforms during development in Drosophila.^

The association between maternal use of selective serotonin reuptake inhibitors during pregnancy and adverse pregnancy outcomes

Maternal use of SSRIs for depression and anxiety during pregnancy has increased over the last decade. Recent studies have questioned the safety of these antidepressants when used in during pregnancy. The aim of this project is to assess the associations between maternal SSRI use and GH, SGA, and preterm birth using data from a U.S. population-based study with self-reported exposure information. ^ The study population is comprised of mothers of control infants from the NBDPS, an ongoing, multi-state, population-based case-control study. Mothers were asked about any use of medications during pregnancy, including the dates they started and stopped taking each medication. Maternal GH was self-reported, while gestational age and birth weight were calculated from information on birth certificates or medical records. ^ Our study found that women exposed to SSRIs in the first trimester and beyond had a higher odds of GH compared to unexposed women (aOR=1.96, 95% CI=1.02-3.74). Women who used SSRIs only in the first trimester had no increased odds of GH (aOR=0.77, 95% CI=0.24-2.50). Women who used SSRIs throughout their entire pregnancy had a two-fold increase in the odds of delivering an SGA infant compared to unexposed women (aOR=2.16, 95% CI=1.01-4.62), while women who reported SSRI use only in the first trimester had a decreased odds of delivering an SGA infant (aOR=0.56, 95% CI=0.14-2.34). Finally, both women who used SSRIs in the first trimester only (aOR=1.58, 95% CI=0.71-3.51) and women who used SSRIs in the first trimester and beyond (aOR=1.49, 95% CI=0.76-2.90) had an increased odds of delivering preterm compared to unexposed women. ^ Results from our study suggest that women who use SSRIs in the first trimester and beyond have an increased and significant odds of GH and SGA. An increase in the odds of preterm birth was also observed among women exposed in this period and is consistent with the results of previous studies which had much larger sample sizes. Women who use SSRIs only in the first trimester appear to have no increased odds of GH or SGA, but may have an increased odds of preterm birth. These findings are consistent with previous studies and highlight how exposure to SSRIs at different points in gestation may result in different risks for these outcomes. ^

Physical activity among breast and prostate cancer survivors: Barriers, facilitators and maintenance following the FRESH START trial

Research provides evidence of the positive health effects associated with regular physical activity participation in all populations. Activity may prove to be especially beneficial in those with chronic conditions such as cancer. However, the majority of cancer patients and survivors do not participate in the recommended amount of physical activity. The purpose of this dissertation was to identify factors associated with physical activity participation, describe how these factors change as result of a diet and exercise intervention, and to evaluate correlates of long term physical activity maintenance. ^ For this dissertation, I analyzed data from the FRESH START trial, a randomized, single-blind, phase II clinical trial focused on improving diet and physical activity among recently diagnosed breast and prostate cancer survivors. Analyses included both parametric and non-parametric statistical tests. Three separate studies were conducted, with sample sizes ranging from 400 to 486. ^ Common barriers to exercise, such as “no willpower,” “too busy,” and “I have pain,” were reported among breast and prostate cancer survivors; however, these barriers were not significantly associated with minutes of physical activity. Breast cancer survivors reported a greater number of total barriers to exercise as well as higher proportions reporting individual barriers, compared to prostate cancer survivors. Just less than half of participants reduced their total number of barriers to exercise from baseline to 1-year follow-up, and those who did reduce barriers reported greater increases in minutes of physical activity compared to those who reported no change in barriers to exercise. Participants in both the tailored and standardized intervention groups reported greater minutes of physical activity at 2-year follow-up compared to baseline. Overall, twelve percent of participants reached recommended levels of physical activity at both 1- and 2-year follow-up. Self-efficacy was positively associated with physical activity maintenance, and the number of total barriers to exercise was inversely associated with physical activity maintenance. ^ Results from this dissertation are novel and informative, and will help to guide future physical activity interventions among cancer survivors. Thoughtfully designed interventions may encourage greater participation in physical activity and ultimately improve overall quality of life in this population. ^

Population-level risks of physical activity: Saving bones and screening hearts

Documented risks of physical activity include reduced bone mineral density at high activity volume, and sudden cardiac death among adults and adolescents. Further illumination of these risks is needed to inform future public health guidelines. The present research seeks to 1) quantify the association between physical activity and bone mineral density (BMD) across a broad range of activity volume, 2) assess the utility of an existing pre-screening questionnaire among US adults, and 3) determine if pre-screening risk stratification by questionnaire predicts referral to physician among Texas adolescents. ^ Among 9,468 adults 20 years of age or older in the National Health and Nutrition Examination Survey (NHANES) 2007-2010, linear regression analyses revealed generally higher BMD at the lumbar spine and proximal femur with greater reported activity volume. Only lumbar BMD in women was unassociated with activity volume. Among men, BMD was similar at activity beyond four times the minimum volume recommended in the Physical Activity Guidelines. These results suggest that the range of activity reported by US adults is not associated with low BMD at either site. ^ The American Heart Association / American College of Sports Medicine Preparticipation Questionnaire (AAPQ) was applied to 6,661 adults 40 years of age or older from NHANES 2001-2004 by using NHANES responses to complete AAPQ items. Following AAPQ referral criteria, 95.5% of women and 93.5% of men would be referred to a physician before exercise initiation, suggesting little utility for the AAPQ among adults aged 40 years or older. Unnecessary referral before exercise initiation may present a barrier to exercise adoption and may strain an already stressed healthcare infrastructure. ^ Among 3181 athletes in the Texas Adolescent Athlete Heart Screening Registry, 55.2% of boys and 62.2% of girls were classified as high-risk based on questionnaire answers. Using sex-stratified contingency table analyses, risk categories were not significantly associated with referral to physician based on electrocardiogram or echocardiogram, nor were they associated with confirmed diagnoses on follow-up. Additional research is needed to identify which symptoms are most closely related to sudden cardiac death, and determine the best methods for rapid and reliable assessment. ^ In conclusion, this research suggests that the volume of activity reported by US adults is not associated with low BMD at two clinically relevant sites, casts doubts on the utility of two existing cardiac screening tools, and raises concern about barriers to activity erected through ineffective screening. These findings augment existing research in this area that may inform revisions to the Physical Activity Guidelines regarding risk mitigation.^

Physico-chemical characteristics and ikaite content of brine and ice samples taken during SIPEX and DDU campaigns in East Antarctica, 2007

Calcium carbonate precipitation in sea ice is thought to potentially drive significant CO2 uptake by the ocean. However, little is known about the quantitative spatial and temporal distribution of CaCO3 within sea ice, although it is hypothesized that high quantities of dissolved organic matter and/or phosphate (common in sea ice) may inhibit its formation. In this quantitative study of hydrous calcium carbonate as ikaite, sea ice cores and brine samples were collected from pack and land fast sea ice between September and December 2007 during two expeditions, one in the East Antarctic sector and the other off Terre Adélie. Samples were analysed for CaCO3, salinity, dissolved organic carbon/nitrogen, inorganic phosphate, and total alkalinity. No relationship between these parameters and CaCO3 precipitation was evident. Ikaite was found mostly in the uppermost layers of sea ice with maximum concentrations of up to 126 mg ikaite per litre melted sea ice being measured, although both the temporal and horizontal spatial distributions of ikaite were highly heterogeneous. The precipitate was also found in the snow on top of the sea ice at some of the sampling locations.