A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers.

Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers

Fitting the Means to the Ends: One School’s Experience with Quantitative and Qualitative Methods in Curriculum Evaluation During Curriculum Change

Curriculum evaluation plays an important role in substantive curriculum change. The experience of the University of Texas Medical Branch (UTMB) with evaluation processes developed for the new Integrated Medical Curriculum (IMC) illustrates how evaluation methods may be chosen to match the goals of the curriculum evaluation process. Quantitative data such as ratings of courses or scores on external exams are useful for comparing courses or assessing whether standards have been met. Qualitative data such as students’ comments about aspects of courses are useful for eliciting explanations of observed phenomena and describing relationships between curriculum features and outcomes. The curriculum evaluation process designed for the IMC used both types of evaluation methods in a complementary fashion. Quantitative and qualitative methods have been used for formative evaluation of the new IMC courses. They are now being incorporated into processes to judge the IMC against its goals and objectives

Effects of Activity and Energy Budget Balancing Algorithm on Laboratory Performance of a Fish Bioenergetics Model

We evaluated the performance of the Wisconsin bioenergetics model for lake trout Salvelinus namaycush that were fed ad libitum in laboratory tanks under regimes of low activity and high activity. In addition, we compared model performance under two different model algorithms: (1) balancing the lake trout energy budget on day t based on lake trout energy density on day t and (2) balancing the lake trout energy budget on day t based on lake trout energy density on day t + 1. Results indicated that the model significantly underestimated consumption for both inactive and active lake trout when algorithm 1 was used and that the degree of underestimation was similar for the two activity levels. In contrast, model performance substantially improved when using algorithm 2, as no detectable bias was found in model predictions of consumption for inactive fish and only a slight degree of overestimation was detected for active fish. The energy budget was accurately balanced by using algorithm 2 but not by using algorithm 1. Based on the results of this study, we recommend the use of algorithm 2 to estimate food consumption by fish in the field. Our study results highlight the importance of accurately accounting for changes in fish energy density when balancing the energy budget; furthermore, these results have implications for the science of evaluating fish bioenergetics model performance and for more accurate estimation of food consumption by fish in the field when fish energy density undergoes relatively rapid changes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141002/1/tafs1328.pd

Dynamic targeting of the replication machinery to sites of DNA damage

Components of the DNA replication machinery localize into discrete subnuclear foci after DNA damage, where they play requisite functions in repair processes. Here, we find that the replication factors proliferating cell nuclear antigen (PCNA) and RPAp34 dynamically exchange at these repair foci with discrete kinetics, and this behavior is distinct from kinetics during DNA replication. Posttranslational modification is hypothesized to target specific proteins for repair, and we find that accumulation and stability of PCNA at sites of damage requires monoubiquitination. Contrary to the popular notion that phosphorylation on the NH2 terminus of RPAp34 directs the protein for repair, we demonstrate that phosphorylation by DNA-dependent protein kinase enhances RPAp34 turnover at repair foci. Together, these findings support a dynamic exchange model in which multiple repair factors regulated by specific modifications have access to and rapidly turn over at sites of DNA damage

Direct Estimation of Evoked Hemoglobin Changes by Multimodality Fusion Imaging

In the last two decades, both diffuse optical tomography (DOT) and blood oxygen level dependent (BOLD)-based functional magnetic resonance imaging (fMRI) methods have been developed as noninvasive tools for imaging evoked cerebral hemodynamic changes in studies of brain activity. Although these two technologies measure functional contrast from similar physiological sources, i.e., changes in hemoglobin levels, these two modalities are based on distinct physical and biophysical principles leading to both limitations and strengths to each method. In this work, we describe a unified linear model to combine the complimentary spatial, temporal, and spectroscopic resolutions of concurrently measured optical tomography and fMRI signals. Using numerical simulations, we demonstrate that concurrent optical and BOLD measurements can be used to create cross-calibrated estimates of absolute micromolar deoxyhemoglobin changes. We apply this new analysis tool to experimental data acquired simultaneously with both DOT and BOLD imaging during a motor task, demonstrate the ability to more robustly estimate hemoglobin changes in comparison to DOT alone, and show how this approach can provide cross-calibrated estimates of hemoglobin changes. Using this multimodal method, we estimate the calibration of the 3tesla BOLD signal to be −0.55%±0.40% signal change per micromolar change of deoxyhemoglobin

Quantum Degenerate Exciton-Polaritons in Thermal Equilibrium

We study the momentum distribution and relaxation dynamics of semiconductor microcavity polaritons by angle-resolved and time-resolved spectroscopy. Above a critical pump level, the thermalization time of polaritons at positive detunings becomes shorter than their lifetime, and the polaritons form a quantum degenerate Bose-Einstein distribution in thermal equilibrium with the lattice.Comment: Updated with the published versio

Quantifying the Lead Time Required for a Linear Trend to Emerge from Natural Climate Variability

This study introduces a simple analytic expression for calculating the lead time required for a linear trend to emerge in a Gaussian first-order autoregressive process. The expression is derived from the standard error of the regression and is tested using the NCAR Community Earth System Model Large Ensemble of climate change simulations. It is shown to provide a robust estimate of the point in time when the forced signal of climate change has emerged from the natural variability of the climate system with a predetermined level of statistical confidence. The expression provides a novel analytic tool for estimating the time of emergence of anthropogenic climate change and its associated regional climate impacts from either observed or modeled estimates of natural variability and trends.National Science Foundation (U.S.). Climate and Large-Scale Dynamics Program (Grant AGS-1419667

Rapid Assessment of Existing HIV Prevention Programming in a Community Mental Health Center

In preparation for implementation of a comprehensive HIV prevention program in a Community Mental Health Center for persons with mental illness who are also abusing substances, a rapid assessment procedure (RAP) of existing prevention services that may have developed in the setting over time was undertaken at baseline. In addition to an ecological assessment of the availability of HIV-related information that was available on-site, in-depth interviews and focus groups were conducted with Center administrators, direct-care staff, and mental health consumers. Results indicated that responses regarding available services differed depending upon type of respondent, with administration reporting greater availability of preventive programs and educational materials than did direct-care staff or mental health consumers themselves. But overall, formalized training on HIV prevention by case managers is extremely rare. Case managers felt that other providers, such as doctors or nurses, were more appropriate to deliver an HIV prevention intervention