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Showing papers by "University of Utah published in 2009"


Journal ArticleDOI
TL;DR: The Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines target the reliability of results to help ensure the integrity of the scientific literature, promote consistency between laboratories, and increase experimental transparency.
Abstract: Background: Currently, a lack of consensus exists on how best to perform and interpret quantitative real-time PCR (qPCR) experiments. The problem is exacerbated by a lack of sufficient experimental detail in many publications, which impedes a reader’s ability to evaluate critically the quality of the results presented or to repeat the experiments. Content: The Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines target the reliability of results to help ensure the integrity of the scientific literature, promote consistency between laboratories, and increase experimental transparency. MIQE is a set of guidelines that describe the minimum information necessary for evaluating qPCR experiments. Included is a checklist to accompany the initial submission of a manuscript to the publisher. By providing all relevant experimental conditions and assay characteristics, reviewers can assess the validity of the protocols used. Full disclosure of all reagents, sequences, and analysis methods is necessary to enable other investigators to reproduce results. MIQE details should be published either in abbreviated form or as an online supplement. Summary: Following these guidelines will encourage better experimental practice, allowing more reliable and unequivocal interpretation of qPCR results.

12,469 citations


Journal ArticleDOI
TL;DR: D diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer.
Abstract: Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression–based “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like. Methods A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. Results The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for t...

3,913 citations


Journal ArticleDOI
TL;DR: This work addresses many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes.
Abstract: The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.

2,093 citations



Journal ArticleDOI
TL;DR: Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories.
Abstract: Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan – Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor – positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal – HER2 positive. Luminal B and luminal – HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer – specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal – HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish

1,966 citations


Journal ArticleDOI
TL;DR: In this paper, it was shown that pl-flips exist in dimension n − 1, assuming finite generation in dimension N − 1 and assuming that pl flips exist in all dimensions.
Abstract: Assuming finite generation in dimension n − 1, we prove that pl-flips exist in dimension n.

1,612 citations


Journal ArticleDOI
TL;DR: Treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, but it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders.
Abstract: Background It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. Methods Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. Results A total of 958 women were randomly assigned to a study group — 485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.1...

1,587 citations


Journal ArticleDOI
TL;DR: This review provides a comprehensive overview of the advancement of functional and genetic studies in the late 1980s and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body.
Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies...

1,561 citations


Journal ArticleDOI
TL;DR: This study establishes a clear link between specific parental and caregiver rejecting behaviors and negative health problems in young lesbian, gay, and bisexual adults and recommends services to educate families about the impact of rejecting behaviors.
Abstract: OBJECTIVE. We examined specific family rejecting reactions to sexual orientation and gender expression during adolescence as predictors of current health problems in a sample of lesbian, gay, and bisexual young adults. METHODS. On the basis of previously collected in-depth interviews, we developed quantitative scales to assess retrospectively in young adults the frequency of parental and caregiver reactions to a lesbian, gay, or bisexual sexual orientation during adolescence. Our survey instrument also included measures of 9 negative health indicators, including mental health, substance abuse, and sexual risk. The survey was administered to a sample of 224 white and Latino self-identified lesbian, gay, and bisexual young adults, aged 21 to 25, recruited through diverse venues and organizations. Participants completed self-report questionnaires by using either computer-assisted or pencil-and-paper surveys. RESULTS. Higher rates of family rejection were significantly associated with poorer health outcomes. On the basis of odds ratios, lesbian, gay, and bisexual young adults who reported higher levels of family rejection during adolescence were 8.4 times more likely to report having attempted suicide, 5.9 times more likely to report high levels of depression, 3.4 times more likely to use illegal drugs, and 3.4 times more likely to report having engaged in unprotected sexual intercourse compared with peers from families that reported no or low levels of family rejection. Latino men reported the highest number of negative family reactions to their sexual orientation in adolescence. CONCLUSIONS. This study establishes a clear link between specific parental and caregiver rejecting behaviors and negative health problems in young lesbian, gay, and bisexual adults. Providers who serve this population should assess and help educate families about the impact of rejecting behaviors. Counseling families, providing anticipatory guidance, and referring families for counseling and support can help make a critical difference in helping decrease risk and increasing well-being for lesbian, gay, and bisexual youth.

1,406 citations


Journal ArticleDOI
28 May 2009-Nature
TL;DR: Several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls, and duplications 55 kilobases upstream of complementary DNA AK123120 indicate that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

1,331 citations


Journal ArticleDOI
TL;DR: These validated prediction rules identified children at very low risk of clinically-important traumatic brain injuries (ciTBI) for whom CT might be unnecessary and missed neurosurgery in validation populations.

Journal ArticleDOI
TL;DR: The results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10−8) and suggest priority targets for study in other auto-immune disorders.
Abstract: Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Journal ArticleDOI
TL;DR: This work presents the first multiplexed QPCR method for telomere length measurement, and shows that a single fluorescent DNA-intercalating dye is sufficient in this system, because T signals can be collected in early cycles, before S signals rise above baseline, and S signals can been collected at a temperature that fully melts the telomeres product, sending its signal to baseline.
Abstract: The current quantitative polymerase chain reaction (QPCR) assay of telomere length measures telomere (T) signals in experimental DNA samples in one set of reaction wells, and single copy gene (S) signals in separate wells, in comparison to a reference DNA, to yield relative T/S ratios that are proportional to average telomere length. Multiplexing this assay is desirable, because variation in the amount of DNA pipetted would no longer contribute to variation in T/S, since T and S would be collected within each reaction, from the same input DNA. Multiplexing also increases throughput and lowers costs, since half as many reactions are needed. Here, we present the first multiplexed QPCR method for telomere length measurement. Remarkably, a single fluorescent DNA-intercalating dye is sufficient in this system, because T signals can be collected in early cycles, before S signals rise above baseline, and S signals can be collected at a temperature that fully melts the telomere product, sending its signal to baseline. The correlation of T/S ratios with Terminal Restriction Fragment (TRF) lengths measured by Southern blot was stronger with this monochrome multiplex QPCR method (R(2) = 0.844) than with our original singleplex method (R(2) = 0.677). Multiplex T/S results from independent runs on different days were highly reproducible (R(2) = 0.91).

Journal ArticleDOI
TL;DR: A life-span perspective on social support and health that takes into account distinct antecedent processes and mechanisms that are related to measures of support over time is argued, highlighting the need to distinguish measures of perceived and received support and its links to more specific diseases.
Abstract: Social support has been reliably related to physical health outcomes. However, the conceptual basis of such links needs greater development. In this article, I argue for a life-span perspective on social support and health that takes into account distinct antecedent processes and mechanisms that are related to measures of support over time. Such a view highlights the need to distinguish measures of perceived and received support and its links to more specific diseases (e.g., chronic, acute) and stages of disease development (e.g., incidence). I discuss both the novel implications of these theoretical arguments for research on social support and physical health, as well as the potential intervention approaches that are apparent from this perspective.

Journal ArticleDOI
TL;DR: This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab with a systematic review of the relevant literature.
Abstract: Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO’s oncologists following publication or presentation of potentially practicechanging data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Clinical Context Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Recent Data

Journal ArticleDOI
23 Jul 2009-Nature
TL;DR: It is shown that the retained nucleosomes are significantly enriched at loci of developmental importance, including imprinted gene clusters, microRNA clusters, HOX genes clusters, and the promoters of stand-alone developmental transcription and signalling factors.
Abstract: Because nucleosomes are widely replaced by protamine in mature human sperm, the epigenetic contributions of sperm chromatin to embryo development have been considered highly limited. Here we show that the retained nucleosomes are significantly enriched at loci of developmental importance, including imprinted gene clusters, microRNA clusters, HOX gene clusters, and the promoters of stand-alone developmental transcription and signalling factors. Notably, histone modifications localize to particular developmental loci. Dimethylated lysine 4 on histone H3 (H3K4me2) is enriched at certain developmental promoters, whereas large blocks of H3K4me3 localize to a subset of developmental promoters, regions in HOX clusters, certain noncoding RNAs, and generally to paternally expressed imprinted loci, but not paternally repressed loci. Notably, trimethylated H3K27 (H3K27me3) is significantly enriched at developmental promoters that are repressed in early embryos, including many bivalent (H3K4me3/H3K27me3) promoters in embryonic stem cells. Furthermore, developmental promoters are generally DNA hypomethylated in sperm, but acquire methylation during differentiation. Taken together, epigenetic marking in sperm is extensive, and correlated with developmental regulators.

Journal ArticleDOI
TL;DR: In this article, it is shown that many of these attractive features of zirconia, especially fracture toughness and strength, are compromised after prolonged exposure to water vapor at intermediate temperatures (∼30°-300°C).
Abstract: Zirconia ceramics have found broad applications in a variety of energy and biomedical applications because of their unusual combination of strength, fracture toughness, ionic conductivity, and low thermal conductivity. These attractive characteristics are largely associated with the stabilization of the tetragonal and cubic phases through alloying with aliovalent ions. The large concentration of vacancies introduced to charge compensate of the aliovalent alloying is responsible for both the exceptionally high ionic conductivity and the unusually low, and temperature independent, thermal conductivity. The high fracture toughness exhibited by many of zirconia ceramics is attributed to the constraint of the tetragonal-to-monoclinic phase transformation and its release during crack propagation. In other zirconia ceramics containing the tetragonal phase, the high fracture toughness is associated with ferroelastic domain switching. However, many of these attractive features of zirconia, especially fracture toughness and strength, are compromised after prolonged exposure to water vapor at intermediate temperatures (∼30°–300°C) in a process referred to as low-temperature degradation (LTD), and initially identified over two decades ago. This is particularly so for zirconia in biomedical applications, such as hip implants and dental restorations. Less well substantiated is the possibility that the same process can also occur in zirconia used in other applications, for instance, zirconia thermal barrier coatings after long exposure at high temperature. Based on experience with the failure of zirconia femoral heads, as well as studies of LTD, it is shown that many of the problems of LTD can be mitigated by the appropriate choice of alloying and/or process control.

Journal ArticleDOI
TL;DR: ABF swimmers represent the first demonstration of microscopic artificial swimmers that use helical propulsion and are of interest in fundamental research and for biomedical applications.
Abstract: Inspired by the natural design of bacterial flagella, we report artificial bacterial flagella (ABF) that have a comparable shape and size to their organic counterparts and can swim in a controllable fashion using weak applied magnetic fields. The helical swimmer consists of a helical tail resembling the dimensions of a natural flagellum and a thin soft-magnetic “head” on one end. The swimming locomotion of ABF is precisely controlled by three orthogonal electromagnetic coil pairs. Microsphere manipulation is performed, and the thrust force generated by an ABF is analyzed. ABF swimmers represent the first demonstration of microscopic artificial swimmers that use helical propulsion. Self-propelled devices such as these are of interest in fundamental research and for biomedical applications.

Journal ArticleDOI
28 May 2009-Nature
TL;DR: The results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to the authors' knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

Journal ArticleDOI
TL;DR: The utility of delayed-enhancement magnetic resonance imaging (DE-MRI) in detecting abnormal atrial tissue before radiofrequency ablation and in predicting procedural outcome is reported and may provide insight into the progress of the disease.
Abstract: Background— Atrial fibrillation (AF) is associated with diffuse left atrial fibrosis and a reduction in endocardial voltage. These changes are indicators of AF severity and appear to be predictors of treatment outcome. In this study, we report the utility of delayed-enhancement magnetic resonance imaging (DE-MRI) in detecting abnormal atrial tissue before radiofrequency ablation and in predicting procedural outcome. Methods and Results— Eighty-one patients presenting for pulmonary vein antrum isolation for treatment of AF underwent 3-dimensional DE-MRI of the left atrium before the ablation. Six healthy volunteers also were scanned. DE-MRI images were manually segmented to isolate the left atrium, and custom software was implemented to quantify the spatial extent of delayed enhancement, which was then compared with the regions of low voltage from electroanatomic maps from the pulmonary vein antrum isolation procedure. Patients were assessed for AF recurrence at least 6 months after pulmonary vein antrum i...

Journal ArticleDOI
TL;DR: Yosso, Smith, Miguel Ceja, and Daniel Solorzano as mentioned in this paper explored and understood incidents of racial microaggressions as experienced by Latina/o students at three selective universities.
Abstract: In this article, Tara Yosso, William Smith, Miguel Ceja, and Daniel Solorzano expand on their previous work by employing critical race theory to explore and understand incidents of racial microaggressions as experienced by Latina/o students at three selective universities. The authors explore three types of racial microaggressions—interpersonal microaggressions, racial jokes, and institutional microaggressions—and consider the effects of these racist affronts on Latina/o students. Challenging the applicability of Vincent Tinto's three stages of passage for college students, the authors explore the processes by which Latinas/os respond to racial microaggressions and confront hostile campus racial climates. The authors find that, through building community and developing critical navigation skills, Latina/o students claim empowerment from the margins.

Journal ArticleDOI
TL;DR: It is shown that mouse fibroblasts expressing wild-type Ire1 but not an Ire1 variant lacking nuclease activity also degrade mRNAs in response to ER stress, suggesting that cells use a multitiered mechanism by which different conditions in the ER lead to distinct outputs from Ire1.
Abstract: Maintenance of endoplasmic reticulum (ER) function is achieved in part through Ire1 (inositol-requiring enzyme 1), a transmembrane protein activated by protein misfolding in the ER. The cytoplasmic nuclease domain of Ire1 cleaves the messenger RNA (mRNA) encoding XBP-1 (X-box-binding protein 1), enabling splicing and production of this active transcription factor. We recently showed that Ire1 activation independently induces the rapid turnover of mRNAs encoding membrane and secreted proteins in Drosophila melanogaster cells through a pathway we call regulated Ire1-dependent decay (RIDD). In this study, we show that mouse fibroblasts expressing wild-type Ire1 but not an Ire1 variant lacking nuclease activity also degrade mRNAs in response to ER stress. Using a second variant of Ire1 that is activated by a small adenosine triphosphate analogue, we show that although XBP-1 splicing can be artificially induced in the absence of ER stress, RIDD appears to require both Ire1 activity and ER stress. Our data suggest that cells use a multitiered mechanism by which different conditions in the ER lead to distinct outputs from Ire1.

Journal ArticleDOI
TL;DR: This study attempts to comprehensively and objectively measure subjective qualities of the urban street environment using ratings from an expert panel to arm researchers with operational definitions they can use to measure the street environment and test for significant associations with walking behaviour.
Abstract: This study attempts to comprehensively and objectively measure subjective qualities of the urban street environment. Using ratings from an expert panel, it was possible to measure five urban design qualities in terms of physical characteristics of streets and their edges: imageability, enclosure, human scale, transparency and complexity. The operational definitions do not always comport with the qualitative definitions, and provide new insights into the nature of these urban design qualities. The immediate purpose of this study is to arm researchers with operational definitions they can use to measure the street environment and test for significant associations with walking behaviour. A validation study is currently underway in New York City. Depending on the outcome of this and other follow-up research, the ultimate purpose would be to inform urban design practice.

Journal ArticleDOI
TL;DR: AAPM Task Group 119 has produced quantitative confidence limits as baseline expectation values for IMRT commissioning and locally derived confidence limits that substantially exceed these baseline values may indicate the need for improved IM RT commissioning.
Abstract: AAPM Task Group 119 has produced quantitative confidence limits as baseline expectation values for IMRT commissioning. A set of test cases was developed to assess the overall accuracy of planning and delivery of IMRT treatments. Each test uses contours of targets and avoidance structures drawn within rectangular phantoms. These tests were planned, delivered, measured, and analyzed by nine facilities using a variety of IMRT planning and delivery systems. Each facility had passed the Radiological Physics Center credentialing tests for IMRT. The agreement between the planned and measured doses was determined using ion chamber dosimetry in high and low dose regions, film dosimetry on coronal planes in the phantom with all fields delivered, and planar dosimetry for each field measured perpendicular to the central axis. The planar dose distributions were assessed using gamma criteria of 3%/3 mm. The mean values and standard deviations were used to develop confidence limits for the test results using the concept confidence limit = /mean/ + 1.96sigma. Other facilities can use the test protocol and results as a basis for comparison to this group. Locally derived confidence limits that substantially exceed these baseline values may indicate the need for improved IMRT commissioning.

Journal ArticleDOI
TL;DR: mW mimics the hydrogen-bonded structure of water through the introduction of a nonbond angular dependent term that encourages tetrahedral configurations, and concludes that it is not the nature of the interactions but the connectivity of the molecules that determines the structural and thermodynamic behavior of water.
Abstract: Water and silicon are chemically dissimilar substances with common physical properties. Their liquids display a temperature of maximum density, increased diffusivity on compression, and they form tetrahedral crystals and tetrahedral amorphous phases. The common feature to water, silicon, and carbon is the formation of tetrahedrally coordinated units. We exploit these similarities to develop a coarse-grained model of water (mW) that is essentially an atom with tetrahedrality intermediate between carbon and silicon. mW mimics the hydrogen-bonded structure of water through the introduction of a nonbond angular dependent term that encourages tetrahedral configurations. The model departs from the prevailing paradigm in water modeling: the use of long-ranged forces (electrostatics) to produce short-ranged (hydrogen-bonded) structure. mW has only short-range interactions yet it reproduces the energetics, density and structure of liquid water, and its anomalies and phase transitions with comparable or better accu...

Journal ArticleDOI
TL;DR: The subtle adjustments needed to ensure developmental plasticity in IUGR are provided by epigenetic modulation of critical genes, accompanied by changes in the quantity and activity of enzymes responsible for making modifications to chromatin as well as global and gene-specific modifications of chromatin.
Abstract: Purpose of review—Intrauterine growth restriction (IUGR) is associated with an increased propensity to develop adult onset disease and is described by the developmental origins of adult disease hypothesis. Sequelae of fetal growth restriction include metabolic disease as well as nonmetabolic disorders. Although it has become clear that the morbidities associated with IUGR are complex and result from disruptions to multiple pathways and multiple organs, the mechanisms driving the long-term effects are only just beginning to be understood. Recent findings—IUGR affects most organ systems by either interrupting developmental processes such as apoptosis or producing lasting changes to levels of key regulatory factors. Both of these are associated with an often persistent change in gene expression. Epigenetic modulation of transcription is a mechanism that is at least partially responsible for this. IUGR is accompanied by changes in the quantity and activity of enzymes responsible for making modifications to chromatin as well as global and gene-specific modifications of chromatin. Summary—The subtle adjustments needed to ensure developmental plasticity in IUGR are provided by epigenetic modulation of critical genes. Translating the messages of the epigenetic profile and identifying the players that mediate the effects remains one of the major challenges in the field. An understanding of the mechanisms driving the epigenetic changes will facilitate identification of dietary and pharmaceutical approaches that can be applied in the postnatal period.

Journal ArticleDOI
TL;DR: Robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements is described, indicating successful long- term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.
Abstract: The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.

Journal ArticleDOI
TL;DR: Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.
Abstract: BACKGROUND Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. METHODS We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU). RESULTS Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. CONCLUSIONS Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.

Journal ArticleDOI
TL;DR: A review of recent literature on coordination in organizations arranged according to the mechanisms that help achieve it can be found in this paper, where the authors propose that coordination mechanisms (such as routines, meetings, plans and schedules) impact the work of organizations by creating three integrative conditions for coordinated activity: accountability, predictability, and common understanding.
Abstract: Coordination, the process of interaction that integrates a collective set of interdependent tasks, is a central purpose of organizations. In this review we begin by discussing the origins of interest in coordination, tracing some of the classic perspectives. We present a review of recent literature on coordination in organizations arranged according to the mechanisms that help achieve it. We then go beyond this review to provide a framework to understand what different coordination mechanisms and activities accomplish. We propose that coordination mechanisms (such as routines, meetings, plans, and schedules) impact the work of organizations by creating three integrative conditions for coordinated activity: accountability, predictability, and common understanding. We end by examining the implications of such a perspective for future research on coordination in organizations.

Journal ArticleDOI
28 Aug 2009-Science
TL;DR: A combination of bioinformatics, yeast genetics, biochemistry, and human genetics was used to show that a previously uncharacterized mitochondrial protein (Sdh5) is required for the activity of respiratory complex II, leading to the discovery of a human tumor susceptibility gene.
Abstract: Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.