The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function

Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.

Iowa Driver’s License Renewal, August 3, 2007

One-on-one communication with driver’s license customers is the most valuable tool Driver Services employees use to help drivers stay independent and safe. Driver Services employees understand that a sense of remaining independent, in everything from running errands to shopping to visits with friends, family and doctors, depends on a driver’s license. There are times when Driver Services personnel, or even the drivers themselves, determine it’s time to stop driving. In those cases, people are given a free identification card. There are also times when the DOT must suspend a person’s driving privilege. This can be caused by vision problems, a medical condition or unsafe driving. If the driver cannot be relicensed, DOT personnel make the commitment to work with the individual by providing information about available transportation alternatives. We are providing this information to make the renewal process understandable and less stressful. We hope that by explaining why the DOT screens vision, requires medical information and requests drive tests, and describing how these all relate to highway safety, drivers will know what to expect. Personnel are available to answer questions or discuss concerns at any of the Iowa Department of Transportation or County Treasurer driver’s license sites. Please contact one of the driver’s license stations listed in this booklet.

Automated Recording of Bridge Inspection Data in the Pontis Format Final Report, HR-364 April 1995

A large percentage of bridges in the state of Iowa are classified as structurally or fiinctionally deficient. These bridges annually compete for a share of Iowa's limited transportation budget. To avoid an increase in the number of deficient bridges, the state of Iowa decided to implement a comprehensive Bridge Management System (BMS) and selected the Pontis BMS software as a bridge management tool. This program will be used to provide a selection of maintenance, repair, and replacement strategies for the bridge networks to achieve an efficient and possibly optimal allocation of resources. The Pontis BMS software uses a new rating system to evaluate extensive and detailed inspection data gathered for all bridge elements. To manually collect these data would be a highly time-consuming job. The objective of this work was to develop an automated-computerized methodology for an integrated data base that includes the rating conditions as defined in the Pontis program. Several of the available techniques that can be used to capture inspection data were reviewed, and the most suitable method was selected. To accomplish the objectives of this work, two userfriendly programs were developed. One program is used in the field to collect inspection data following a step-by-step procedure without the need to refer to the Pontis user's manuals. The other program is used in the office to read the inspection data and prepare input files for the Pontis BMS software. These two programs require users to have very limited knowledge of computers. On-line help screens as well as options for preparing, viewing, and printing inspection reports are also available. The developed data collection software will improve and expedite the process of conducting bridge inspections and preparing the required input files for the Pontis program. In addition, it will eliminate the need for large storage areas and will simplify retrieval of inspection data. Furthermore, the approach developed herein will facilitate transferring these captured data electronically between offices within the Iowa DOT and across the state.

U.S.-Norway Comparison of Interval Breast Cancers

Background: Publications from the International Breast Screening Network (IBSN) have shown that varying definitions create hurdles for comparison of screening performance. Interval breast cancer rates are particularly affected. Objective: to test whether variations in definition of interval cancer rates (ICR) affect comparisons of international ICR, specific to a comparison of ICR in Norway and North Carolina (NC). Methods: An interval cancer (IC) was defined as a cancer diagnosed following a negative screening mammogram in a defined follow-up period. ICR was calculated for women ages 50-69, at subsequent screening in Norway and NC, during the time period 1996 - 2002. ICR was defined using three different denominators (negative screens, negative final assessments and all screens) and three different numerators (DCIS, invasive cancer and all cancers). ICR was then calculated with two methods: 1) number of ICs divided by the number of screens, and ICs divided by the number of women-years at risk for IC. Results: There were no differences in ICR depending on the definition used. In the 1-12 month follow up period ICR (based on number of screens) were: 0.53, 0.54, and 0.54 for Norway; and 1.20, 1.25 and 1.17 for NC, for negative screens, negative final assessment and all screens, respectively: The same trend was seen for 13-24 and 1-24 months follow-up. Using women-years for the analysis did not change the trend. ICR was higher in NC compared to Norway under all definitions and in all follow-up time periods, regardless of calculation method. Conclusion: The ICR within or between Norway and NC did not differ by definition used. ICR were higher in NC than Norway. There are many potential explanations for the difference.

Objective assessment of image quality in conventional and digital mammography taking into account dynamic range.

The goal of this work is to develop a method to objectively compare the performance of a digital and a screen-film mammography system in terms of image quality. The method takes into account the dynamic range of the image detector, the detection of high and low contrast structures, the visualisation of the images and the observer response. A test object, designed to represent a compressed breast, was constructed from various tissue equivalent materials ranging from purely adipose to purely glandular composition. Different areas within the test object permitted the evaluation of low and high contrast detection, spatial resolution and image noise. All the images (digital and conventional) were captured using a CCD camera to include the visualisation process in the image quality assessment. A mathematical model observer (non-prewhitening matched filter), that calculates the detectability of high and low contrast structures using spatial resolution, noise and contrast, was used to compare the two technologies. Our results show that for a given patient dose, the detection of high and low contrast structures is significantly better for the digital system than for the conventional screen-film system studied. The method of using a test object with a large tissue composition range combined with a camera to compare conventional and digital imaging modalities can be applied to other radiological imaging techniques. In particular it could be used to optimise the process of radiographic reading of soft copy images.

Host Genes Important to HIV Replication and Evolution.

Recent years have seen a significant increase in understanding of the host genetic and genomic determinants of susceptibility to HIV-1 infection and disease progression, driven in large part by candidate gene studies, genome-wide association studies, genome-wide transcriptome analyses, and large-scale in vitro genome screens. These studies have identified common variants in some host loci that clearly influence disease progression, characterized the scale and dynamics of gene and protein expression changes in response to infection, and provided the first comprehensive catalogs of genes and pathways involved in viral replication. Experimental models of AIDS and studies in natural hosts of primate lentiviruses have complemented and in some cases extended these findings. As the relevant technology continues to progress, the expectation is that such studies will increase in depth (e.g., to include host whole exome and whole genome sequencing) and in breadth (in particular, by integrating multiple data types).

FAM-MDR: a flexible family-based multifactor dimensionality reduction technique to detect epistasis using related individuals

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

Comparing interval breast cancer rates in Norway and North Carolina: results and challenges.

OBJECTIVE: To compare interval breast cancer rates (ICR) between a biennial organized screening programme in Norway and annual opportunistic screening in North Carolina (NC) for different conceptualizations of interval cancer. SETTING: Two regions with different screening practices and performance. METHODS: 620,145 subsequent screens (1996-2002) performed in women aged 50-69 and 1280 interval cancers were analysed. Various definitions and quantification methods for interval cancers were compared. RESULTS: ICR for one year follow-up were lower in Norway compared with NC both when the rate was based on all screens (0.54 versus 1.29 per 1000 screens), negative final assessments (0.54 versus 1.29 per 1000 screens), and negative screening assessments (0.53 versus 1.28 per 1000 screens). The rate of ductal carcinoma in situ was significantly lower in Norway than in NC for cases diagnosed in both the first and second year after screening. The distributions of histopathological tumour size and lymph node involvement in invasive cases did not differ between the two regions for interval cancers diagnosed during the first year after screening. In contrast, in the second year after screening, tumour characteristics remained stable in Norway but became prognostically more favorable in NC. CONCLUSION: Even when applying a common set of definitions of interval cancer, the ICR was lower in Norway than in NC. Different definitions of interval cancer did not influence the ICR within Norway or NC. Organization of screening and screening performance might be major contributors to the differences in ICR between Norway and NC.

Prévention de la malaria pour les séjours de tongue durée [Malaria prevention for long-term travelers]

The risk of malaria increases with the duration of stay. Long-term travelers need to know the risk of malaria and the effective measures to reduce this risk: personal protective measures against mosquito bites and chemoprophylaxis. The use of insecticide-impregnated mosquito nets and window screens should be emphasized. When chemoprophylaxis is indicated it should be prescribed at least for the first 3 to 6 months. Then, alternative strategies can be discussed with the traveler: continuous chemoprophylaxis, seasonal chemoprophylaxis and/or standby emergency treatment.

Host genetics and HIV-1: the final phase?

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.

Arabidopsis jasmonate signaling pathway.

Jasmonates control defense gene expression and male fertility in the model plant Arabidopsis thaliana. In both cases, the involvement of the jasmonate pathway is complex, involving large-scale transcriptional reprogramming. Additionally, jasmonate signaling is hard-wired into the auxin, ethylene, and salicylate signal networks, all of which are under intense investigation in Arabidopsis. In male fertility, jasmonic acid (JA) is the essential signal intervening both at the level of anther elongation and in pollen dehiscense. A number of genes potentially involved in jasmonate-dependent anther elongation have recently been discovered. In the case of defense, at least two jasmonates, JA and its precursor 12-oxo-phytodienoic acid (OPDA), are necessary for the fine-tuning of defense gene expression in response to various microbial pathogens and arthropod herbivores. However, only OPDA is required for full resistance to some insects and fungi. Other jasmonates probably affect yet more physiological responses. A series of breakthroughs have identified the SKP/CULLIN/F-BOX (SCF), CORONATINE INSENSITIVE (COI1) complex, acting together with the CONSTITUTIVE PHOTOMORPHOGENIC 9 (COP9) signalosome, as central regulatory components of jasmonate signaling in Arabidopsis. The studies, mostly involving mutational approaches, have paved the way for suppressor screens that are expected to further extend our knowledge of jasmonate signaling. When these and other new mutants affecting jasmonate signaling are characterized, new nodes will be added to the Arabidopsis Jasmonate Signaling Pathway Connections Map, and the lists of target genes regulated by jasmonates in Arabidopsis will be expanded.

A comparison of the imaging characteristics of the new Kodak Hyper Speed G film with the current T-MAT G/RA film and the CR 9000 system.

Three standard radiation qualities (RQA 3, RQA 5 and RQA 9) and two screens, Kodak Lanex Regular and Insight Skeletal, were used to compare the imaging performance and dose requirements of the new Kodak Hyper Speed G and the current Kodak T-MAT G/RA medical x-ray films. The noise equivalent quanta (NEQ) and detective quantum efficiencies (DQE) of the four screen-film combinations were measured at three gross optical densities and compared with the characteristics for the Kodak CR 9000 system with GP (general purpose) and HR (high resolution) phosphor plates. The new Hyper Speed G film has double the intrinsic sensitivity of the T-MAT G/RA film and a higher contrast in the high optical density range for comparable exposure latitude. By providing both high sensitivity and high spatial resolution, the new film significantly improves the compromise between dose and image quality. As expected, the new film has a higher noise level and a lower signal-to-noise ratio than the standard film, although in the high frequency range this is compensated for by a better resolution, giving better DQE results--especially at high optical density. Both screen-film systems outperform the phosphor plates in terms of MTF and DQE for standard imaging conditions (Regular screen at RQA 5 and RQA 9 beam qualities). At low energy (RQA 3), the CR system has a comparable low-frequency DQE to screen-film systems when used with a fine screen at low and middle optical densities, and a superior low-frequency DQE at high optical density.

Construction mechanisms and thermal evolution of upper crustal intrusions : the Saint-Jean-du-Doigt bimodal intrusion (Brittany, France)

Understanding the emplacement and growth of intrusive bodies in terms of mechanism, duration, ther¬mal evolution and rates are fundamental aspects of crustal evolution. Recent studies show that many plutons grow in several Ma by in situ accretion of discrete magma pulses, which constitute small-scale magmatic reservoirs. The residence time of magmas, and hence their capacities to interact and differentiate, are con¬trolled by the local thermal environment. The latter is highly dependant on 1) the emplacement depth, 2) the magmas and country rock composition, 3) the country rock thermal conductivity, 4) the rate of magma injection and 5) the geometry of the intrusion. In shallow level plutons, where magmas solidify quickly, evi¬dence for magma mixing and/or differentiation processes is considered by many authors to be inherited from deeper levels. This work shows however that in-situ differentiation and magma interactions occurred within basaltic and felsic sills at shallow depth (0.3 GPa) in the St-Jean-du-Doigt (SJDD) bimodal intrusion, France. This intrusion emplaced ca. 347 Ma ago (IDTIMS U/Pb on zircon) in the Precambrian crust of the Armori- can massif and preserves remarkable sill-like emplacement processes of bimodal mafic-felsic magmas. Field evidence coupled to high precision zircon U-Pb dating document progressive thermal maturation within the incrementally built ioppolith. Early m-thick mafic sills (eastern part) form the roof of the intrusion and are homogeneous and fine-grained with planar contacts with neighboring felsic sills; within a minimal 0.8 Ma time span, the system gets warmer (western part). Sills are emplaced by under-accretion under the old east¬ern part, interact and mingle. A striking feature of this younger, warmer part is in-situ differentiation of the mafic sills in the top 40 cm of the layer, which suggests liquids survival in the shallow crust. Rheological and thermal models were performed in order to determine the parameters required to allow this observed in- situ differentiation-accumulation processes. Strong constraints such as total emplacement durations (ca. 0.8 Ma, TIMS date) and pluton thickness (1.5 Km, gravity model) allow a quantitative estimation of the various parameters required (injection rates, incubation time,...). The results show that in-situ differentiation may be achieved in less than 10 years at such shallow depth, provided that: (1) The differentiating sills are injected beneath consolidated, yet still warm basalt sills, which act as low conductive insulating screens (eastern part formation in the SJDD intrusion). The latter are emplaced in a very short time (800 years) at high injection rate (0.5 m/y) in order to create a "hot zone" in the shallow crust (incubation time). This implies that nearly 1/3 of the pluton (400m) is emplaced by a subsequent and sustained magmatic activity occurring on a short time scale at the very beginning of the system. (2) Once incubation time is achieved, the calculations show that a small hot zone is created at the base of the sill pile, where new injections stay above their solidus T°C and may interact and differentiate. Extraction of differentiated residual liquids might eventually take place and mix with newly injected magma as documented in active syn-emplacement shear-zones within the "warm" part of the pluton. (3) Finally, the model show that in order to maintain a permanent hot zone at shallow level, injection rate must be of 0.03 m/y with injection of 5m thick basaltic sills eveiy 130yr, imply¬ing formation of a 15 km thick pluton. As this thickness is in contradiction with the one calculated for SJDD (1.5 Km) and exceed much the average thickness observed for many shallow level plutons, I infer that there is no permanent hot zone (or magma chambers) at such shallow level. I rather propose formation of small, ephemeral (10-15yr) reservoirs, which represent only small portions of the final size of the pluton. Thermal calculations show that, in the case of SJDD, 5m thick basaltic sills emplaced every 1500 y, allow formation of such ephemeral reservoirs. The latter are formed by several sills, which are in a mushy state and may interact and differentiate during a short time.The mineralogical, chemical and isotopic data presented in this study suggest a signature intermediate be¬tween E-MORB- and arc-like for the SJDD mafic sills and feeder dykes. The mantle source involved produced hydrated magmas and may be astenosphere modified by "arc-type" components, probably related to a sub¬ducting slab. Combined fluid mobile/immobile trace elements and Sr-Nd isotopes suggest that such subduc¬tion components are mainly fluids derived from altered oceanic crust with minor effect from the subducted sediments. Close match between the SJDD compositions and BABB may point to a continental back-arc setting with little crustal contamination. If so, the SjDD intrusion is a major witness of an extensional tectonic regime during the Early-Carboniferous, linked to the subduction of the Rheno-Hercynian Ocean beneath the Variscan terranes. Also of interest is the unusual association of cogenetic (same isotopic compositions) K-feldspar A- type granite and albite-granite. A-type granites may form by magma mixing between the mafic magma and crustal melts. Alternatively, they might derive from the melting of a biotite-bearing quartz-feldspathic crustal protolith triggered by early mafic injections at low crustal levels. Albite-granite may form by plagioclase cu¬mulate remelting issued from A-type magma differentiation.

An analysis of patients' understanding of 'routine' preoperative blood tests and HIV screening. Is no news really good news?

OBJECTIVES: Many patients may believe that HIV screening is included in routine preoperative work-ups. We examined what proportion of patients undergoing preoperative blood testing believed that they had been tested for HIV. METHODS: All patients hospitalized for elective orthopaedic surgery between January and December 2007 were contacted and asked to participate in a 15-min computer-assisted telephone interview (n = 1330). The primary outcome was to determine which preoperative tests patients believed had been performed from a choice of glucose, clotting, HIV serology and cholesterol, and what percentage of patients interpreted the lack of result communication as a normal or negative test. The proportion of patients agreeable to HIV screening prior to future surgery was also determined. RESULTS: A total of 991 patients (75%) completed the questionnaire. Three hundred and seventy-five of these 991 patients (38%) believed incorrectly that they had been tested for HIV preoperatively. Younger patients were significantly more likely to believe that an HIV test had been performed (mean age 46 vs. 50 years for those who did not believe that an HIV test had been performed; P < 0.0001). Of the patients who believed that a test had been performed but received no result, 96% interpreted lack of a result as a negative HIV test. Over 80% of patients surveyed stated that they would agree to routine HIV screening prior to future surgery. A higher acceptance rate was associated with younger age (mean age 47 years for those who would agree vs. 56 years for those who would not; P < 0.0001) and male sex ( P < 0.009). CONCLUSIONS: Many patients believe that a preoperative blood test routinely screens for HIV. The incorrect assumption that a lack of result communication indicates a negative test may contribute to delays in HIV diagnoses.

Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies.

STUDY OBJECTIVES: Traditionally, sleep studies in mammals are performed using electroencephalogram/electromyogram (EEG/EMG) recordings to determine sleep-wake state. In laboratory animals, this requires surgery and recovery time and causes discomfort to the animal. In this study, we evaluated the performance of an alternative, noninvasive approach utilizing piezoelectric films to determine sleep and wakefulness in mice by simultaneous EEG/EMG recordings. The piezoelectric films detect the animal's movements with high sensitivity and the regularity of the piezo output signal, related to the regular breathing movements characteristic of sleep, serves to automatically determine sleep. Although the system is commercially available (Signal Solutions LLC, Lexington, KY), this is the first statistical validation of various aspects of sleep. DESIGN: EEG/EMG and piezo signals were recorded simultaneously during 48 h. SETTING: Mouse sleep laboratory. PARTICIPANTS: Nine male and nine female CFW outbred mice. INTERVENTIONS: EEG/EMG surgery. MEASUREMENTS AND RESULTS: The results showed a high correspondence between EEG/EMG-determined and piezo-determined total sleep time and the distribution of sleep over a 48-h baseline recording with 18 mice. Moreover, the piezo system was capable of assessing sleep quality (i.e., sleep consolidation) and interesting observations at transitions to and from rapid eye movement sleep were made that could be exploited in the future to also distinguish the two sleep states. CONCLUSIONS: The piezo system proved to be a reliable alternative to electroencephalogram/electromyogram recording in the mouse and will be useful for first-pass, large-scale sleep screens for genetic or pharmacological studies. CITATION: Mang GM, Nicod J, Emmenegger Y, Donohue KD, O'Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies.