TRANSCRIPTIONAL AND TRANSLATIONAL CONTROL OF ZEBRAFISH MESODERMAL DEVELOPMENT

Establishment of the mesodermal germ layer is a process dependent on the integration of multiple transcriptional and signaling inputs. Here I investigate the role of the transcription factor FoxD3 in zebrafish mesodermal development. FoxD3 gain-of-function results in dorsal mesoderm expansion and body axis dorsalization. FoxD3 knockdown results in axial defects similar to Nodal loss-of-function, and was rescued by Nodal pathway activation. In Nodal mutants, FoxD3 did not rescue mesodermal or axial defects. Therefore, FoxD3 functions through the Nodal pathway and is essential for dorsal mesoderm formation. The FoxD3 mutant, sym1, previously described as a null mutation with neural crest defects, was reported to have no mesodermal or axial phenotypes. We find that Sym1 protein retains activity and induces mesodermal expansion and axial dorsalization. A subset of sym1 homozygotes display axial and mesodermal defects, and penetrance of these phenotypes is enhanced by FoxD3 knockdown in mutant embryos. Therefore, sym1 is a hypomorphic allele, and reduced FoxD3 function results in reduced cyclops expression and subsequent mesodermal and axial defects. The sym1 molecular lesion, a point deletion leading to a seven codon frameshift and premature termination, is predicted to be a truncated protein lacking part of the DNA-binding domain and an essential Groucho corepressor interaction domain (GEH). Strongly predicted to be functionally inactive, the hypomorphic character of sym1 suggested that a -1 translational frameshift may correct the reading frame and produce functional protein. Consistent with this hypothesis, mutation of the distal GEH ablated sym1 cDNA activity. Within the frameshift region are three rarely used codons predicted to cause ribosomal pausing and promote translational frameshifting. Conversion of these codons to highly used codons encoding the same residues rendered the sym1 cDNA inactive. Biochemical analyses confirm that a full length FoxD3 protein is produced from sym1 cDNA, but not when the rare codons are replaced. These results indicate that the null character of the sym1 mutation is suppressed by a novel translational frameshifting mechanism, and support the conclusion that FoxD3 is a Nodal-dependent regulator of zebrafish mesodermal development

MyCourseMap: an interactive visual map to increase curriculum transparency for university students and staff

MyCourseMap is an interactive curriculum map created to increase curriculum transparency for both students and staff. It provides access to the entire curriculum at a glance, displays alignment of unit learning outcomes, assessments, course learning outcomes, and graduate attributes and links video from employers, graduates and students to help students reflect on the curriculum and its relevance. A prototype developed for the Bachelor of Pharmacy course at Curtin University as a proof-of-concept was tested and evaluated in 2014 and 2015. This evaluation utilised a mixed-methods approach using a blend of quantitative and qualitative data through online survey and structured focus group discussions. From the evaluation, the perceived benefits of the MyCourseMap include students’ increased understanding of their degree structure and its relevance to their chosen profession. From a staff perspective, the MyCourseMap helps with review and development of curriculum and professional accreditation. Barriers and challenges have led to prototype refinements

Increased Action Potential Firing Rates of Layer 2/3 Pyramidal Cells in the Prefrontal Cortex are Significantly Related to Cognitive Performance in Aged Monkeys

The neurobiological substrates of significant age-related deficits in higher cognitive abilities mediated by the prefrontal cortex (PFC) are unknown. To address this issue, whole-cell current-clamp recordings were used to compare the intrinsic membrane and action potential (AP) firing properties of layer 2/3 pyramidal cells in PFC slices from young and aged behaviorally characterized rhesus monkeys. Most aged subjects demonstrated impaired performance in Delayed Non-Match to Sample (DNMS) task acquisition, DNMS 2 min delay and the Delayed Recognition Span task. Resting membrane potential and membrane time constant did not differ in aged relative to young cells, but input resistance was significantly greater in aged cells. Single APs did not differ in terms of threshold, duration or rise time, but their amplitude and fall time were significantly decreased in aged cells. Repetitive AP firing rates were significantly increased in aged cells. Within the aged group, there was a U-shaped quadratic relationship between firing rate and performance on each behavioral task. Subjects who displayed either low or very high firing rates exhibited poor performance, while those who displayed intermediate firing rates exhibited relatively good performance. These data indicate that an increase in AP firing rate may be responsible, in part, for age-related PFC dysfunction

Investigating Social Ecological Contributors to Diabetes within Hispanics in an Underserved U.S.-Mexico Border Community

Hispanics bear a disproportionate burden of diabetes in the United States, yet relations of structural, socio-cultural and behavioral factors linked to diabetes are not fully understood across all of their communities. The current study examines disparities and factors associated with diabetes in adult Hispanics of Mexican-descent (N = 648) participating in a population survey of an underserved rural U.S.-Mexico border community. The overall rate of diabetes prevalence rate in the sample, based on self-report and a glucose testing, was 21%; much higher than rates reported for U.S. adults overall, for all Hispanic adults, or for Mexican American adults specifically. Acculturation markers and social determinants of health indicators were only significantly related to diabetes in models not accounting for age. Older age, greater BMI (>30), greater waist-to-hip ratio as well as lower fruit and vegetable consumption were significantly related to increased likelihood of diabetes when all structural, cultural, behavioral, and biological factors were considered. Models with sets of behavioral factors and biological factors each significantly improved explanation of diabetes relative to prior social ecological theory-guided models. The findings show a critical need for diabetes prevention efforts in this community and suggest that health promotion efforts should particularly focus on increasing fruit and vegetable consumption

Unification and the Hierarchy from AdS5

In AdS5, the coupling for bulk gauge bosons runs logarithmically, not as a power law. For this reason, one can preserve perturbative unification of couplings. Depending on the cutoff, this can occur at a high scale. We discuss subtleties in the calculation and present a regularization scheme motivated by the holographic correspondence. We find that generically, as in the standard model, the couplings almost unify. For specific choices of the cutoff and number of scalar multiplets, there is good agreement between the measured couplings and the assumption of high scale unification.Comment: 5 pages, 2 figure

Evidence for Long-Term Impact of Pasos Adelante: Using a Community-Wide Survey to Evaluate Chronic Disease Risk Modification in Prior Program Participants

Effective community-level chronic disease prevention is critical to population health within developed and developing nations. Pasos Adelante is a preventive intervention that aims to reduce chronic disease risk with evidence of effectiveness in US-Mexico residing, Mexican origin, participants. This intervention and related ones also implemented with community health workers have been shown to improve clinical, behavioral and quality of life indicators; though most evidence is from shorter-term evaluations and/or lack comparison groups. The current study examines the impact of this program using secondary data collected in the community 3–6 years after all participants completed the program. A proportional household survey (N = 708) was used that included 48 respondents who indicated they had participated in Pasos. Using propensity score matching to account for differences in program participants versus other community residents (the program targeted those with diabetes and associated risk factors), 148 natural controls were identified for 37 matched Pasos participants. Testing a range of behavioral and clinical indicators of chronic disease risk, logistic regression models accounting for selection bias showed two significant findings; Pasos participants were more physically active and drank less whole milk. These findings add to the evidence of the effectiveness of Pasos Adalente and related interventions in reducing chronic disease risk in Mexican-origin populations, and illustrate the use of innovative techniques for using secondary, community-level data to complement prior evaluation research

Does the Method of Biopsy Affect the Incidence of Sentinel Lymph Node Metastases?

More detailed examination of the sentinel lymph node (SLN) in breast cancer has raised concerns about the clinical significance of micrometastases, specifically isolated tumor cells detected only through immunohistochemical (IHC) staining. It has been suggested that these cells do not carry the same biologic implications as true metastatic foci and may represent artifact. A retrospective institutional review board-approved review was conducted on clinically node-negative breast cancer patients who underwent SLN biopsy (SLNB) between 1997 and 2003. Retrospective analysis of tumor characteristics and the method of the initial diagnostic biopsy were correlated with the presence and nature of metastatic disease in the SLN. Of 537 SLNBs, 123 (23%) were hematoxylin-eosin (H&E) positive. SLN positivity strongly correlated with tumor size (p < 0.001) and tumor grade (p = 0.025), but not with the method of biopsy (needle versus excisional biopsy). Prior to July 2002, we routinely evaluated H&E-negative SLNs with IHC ( n  = 381). Of the 291 H&E-negative patients, 26 had IHC-only detected micrometastases (9%). The likelihood of detecting IHC-only metastases did not correlate with tumor size or grade, but was significantly higher in patients undergoing excisional biopsy than core needle biopsy. While the method of biopsy has no demonstrable effect on the likelihood of finding metastases in the SLN by routine serial sectioning and H&E staining, it may significantly impact the likelihood of finding micrometastases by IHC. IHC should not be used routinely in the evaluation of the SLN and caution should be used when basing treatment decisions (completion axillary lymph node dissection or adjuvant therapy) on IHC-only detected micrometastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72849/1/j.1075-122X.2006.00179.x.pd

b→sb \to s Transitions in Family-dependent U(1)′U(1)^\prime Models

We analyze flavor-changing-neutral-current (FCNC) effects in the $b\to s$ transitions that are induced by family non-universal $U(1)'$ gauge symmetries. After systematically developing the necessary formalism, we present a correlated analysis for the $\Delta B =1, 2$ processes. We adopt a model-independent approach in which we only require family-universal charges for the first and second generations and small fermion mixing angles. We analyze the constraints on the resulting parameter space from $B_s - \bar B_s$ mixing and the time-dependent CP asymmetries of the penguin-dominated $B_d \to (\pi, \phi, \eta', \rho, \omega, f_0)K_S$ decays. Our results indicate that the currently observed discrepancies in some of these modes with respect to the Standard Model predictions can be consistently accommodated within this general class of models.Comment: 36 pages, 11 figure

Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion

INTRODUCTION: Our previous studies detected focal disruptions in myoepithelial cell layers of several ducts with carcinoma in situ. The cell cluster overlying each of the myoepithelial disruptions showed a marked reduction in or a total loss of immunoreactivity for the estrogen receptor (ER). This is in contrast to the adjacent cells within the same duct, which were strongly immunoreactive for the ER. The current study attempts to confirm and expand previous observations on a larger scale. METHODS: Paraffin sections from 220 patients with ER-positive intraductal breast tumors were double immunostained with the same protocol previously used. Cross-sections of ducts lined by ≥ 40 epithelial cells were examined for myoepithelial cell layer disruptions and for ER expression. In five selected cases, ER-negative cells overlying the disrupted myoepithelial cell layer and adjacent ER-positive cells within the same duct were separately microdissected and assessed for loss of heterozygosity and microsatellite instability. RESULTS: Of the 220 cases with 5698 duct cross-sections examined, 94 showed disrupted myoepithelial cell layers with 405 focal disruptions. Of the 94 cases, 79 (84%) contained only ER-negative cell clusters, nine (9.6%) contained both ER-negative and ER-positive cell clusters, and six (6.4%) contained only ER-positive cell clusters overlying disrupted myoepithelial cell layers. Of the 405 disruptions, 350 (86.4%) were overlain by ER-negative cell clusters and 55 (13.6%) were overlain by ER-positive cell clusters (P < 0.01). Microdissected ER-negative and ER-positive cells within the same duct from all five selected cases displayed a different frequency or pattern of loss of heterozygosity and/or microsatellite instability at 10 of the 15 DNA markers. CONCLUSIONS: Cells overlying focally disrupted myoepithelial layers and their adjacent counterparts within the same duct displayed different immunohistochemical and molecular features. These features potentially represent an early sign of the formation of a biologically more aggressive cell clone and the myoepithelial cell layer breakdown possibly associated with tumor progression or invasion