Water-Quality and -Quantity Data for Abandoned Underground Coal Mines in Eastern Kentucky

Water-quality and -quantity analyses were performed between 1997 and 2003 by the Kentucky Geological Survey under contract from the Kentucky River Authority and the Kentucky Infrastructure Authority to study abandoned underground coal mines as possible water supplies for communities in the Eastern Kentucky Coal Field. The steep terrain of the coal field limits surface-water supplies, and groundwater systems are difficult to locate and often have too low a yield to provide community water supplies. KGS has been working with the Kentucky River Authority, the Kentucky Infrastructure Authority, and local government officials to search for water supplies in abandoned underground coal mines. The data in the appendices of this report are interpreted in Cumbie and others (2006)

Hydrophobic and Charged Residues in the C-Terminal Arm of Hepatitis C Virus RNA-Dependent RNA Polymerase Regulate Initiation and Elongation.

The RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is essential for viral genome replication. Crystal structures of the HCV RdRp reveal two C-terminal features, a β-loop and a C-terminal arm, suitably located for involvement in positioning components of the initiation complex. Here we show that these two elements intimately regulate template and nucleotide binding, initiation, and elongation. We constructed a series of β-loop and C-terminal arm mutants, which were used for in vitro analysis of RdRp de novo initiation and primer extension activities. All mutants showed a substantial decrease in initiation activities but a marked increase in primer extension activities, indicating an ability to form more stable elongation complexes with long primer-template RNAs. Structural studies of the mutants indicated that these enzyme properties might be attributed to an increased flexibility in the C-terminal features resulting in a more open polymerase cleft, which likely favors the elongation process but hampers the initiation steps. A UTP cocrystal structure of one mutant shows, in contrast to the wild-type protein, several alternate conformations of the substrate, confirming that even subtle changes in the C-terminal arm result in a more loosely organized active site and flexible binding modes of the nucleotide. We used a subgenomic replicon system to assess the effects of the same mutations on viral replication in cells. Even the subtlest mutations either severely impaired or completely abolished the ability of the replicon to replicate, further supporting the concept that the correct positioning of both the β-loop and C-terminal arm plays an essential role during initiation and in HCV replication in general. IMPORTANCE: HCV RNA polymerase is a key target for the development of directly acting agents to cure HCV infections, which necessitates a thorough understanding of the functional roles of the various structural features of the RdRp. Here we show that even highly conservative changes, e.g., Tyr→Phe or Asp→Glu, in these seemingly peripheral structural features have profound effects on the initiation and elongation properties of the HCV polymerase

Almost Linear B\"uchi Automata

We introduce a new fragment of Linear temporal logic (LTL) called LIO and a new class of Buechi automata (BA) called Almost linear Buechi automata (ALBA). We provide effective translations between LIO and ALBA showing that the two formalisms are expressively equivalent. While standard translations of LTL into BA use some intermediate formalisms, the presented translation of LIO into ALBA is direct. As we expect applications of ALBA in model checking, we compare the expressiveness of ALBA with other classes of Buechi automata studied in this context and we indicate possible applications

Complexidade e escala na investigação da eficácia do ensino: reflexões do estudo MET

Researchers and policymakers in the US and beyond increasingly seek to identify teaching qualities that are associated with academic achievement gains for K-12 students through effectiveness studies. Yet teaching quality varies with academic content and social contexts, involves multiple participants, and requires a range of skills, knowledge, and dispositions. In this essay, we address the inescapable tension between complexity and scale in research on teaching effectiveness. We provide five recommendations to study designers and analysts to manage this tension to enhance effectiveness research, drawing on our recent experiences as the first external analysts of the Measures of Effective Teaching (MET) study. Our recommendations address conceptual framing, the measurement of teaching (e.g., observation protocols, student surveys), sampling, classroom videoing, and the use and interpretation of value-added models.Investigadores y legisladores en los Estados Unidos y en otros países buscan identificar las cualidades de la enseñanza que se asocian con incrementos de desempeño académico para alumnos de primaria y secundaria a través de estudios de eficacia. Sin embargo, la calidad de la enseñanza varía según el contenido académico y los contextos sociales, involucra a múltiples participantes y requiere una variedad de habilidades, conocimientos y disposiciones. En este ensayo, abordamos la ineludible tensión entre la complejidad y la escala en la investigación sobre la eficacia de la enseñanza. Proveemos cinco recomendaciones a los diseñadores de estudios y analistas para manejar esta tensión y mejorar la investigación de eficacia, aprovechando nuestras experiencias recientes como los primeros analistas externos del estudio Measures of Effective Teaching (MET). Nuestras recomendaciones abordan el marco conceptual, la medición de la enseñanza (por ej., protocolos de observación, encuestas de estudiantes), el muestreo, el video en el aula y el uso e interpretación de modelos de valor agregado.Pesquisadores e legisladores nos Estados Unidos e em outros países buscam identificar as qualidades de ensino associadas ao aumento do desempenho acadêmico de alunos do ensino fundamental e médio por meio de estudos de eficácia. No entanto, a qualidade do ensino varia de acordo com o conteúdo acadêmico e os contextos sociais, envolve múltiplos participantes e requer uma variedade de habilidades, conhecimentos e disposições. Neste ensaio, abordamos a tensão inescapável entre complexidade e escala na pesquisa sobre a eficácia do ensino. Fornecemos cinco recomendações para projetistas e analistas de estudo para gerenciar essa tensão e melhorar a pesquisa sobre eficácia, alavancando nossas experiências recentes como os primeiros analistas externos do estudo Measures of Effective Teaching (MET). Nossas recomendações abordam a estrutura conceitual, a medição do ensino (por exemplo, protocolos de observação, pesquisas com estudantes), amostragem, vídeo em sala de aula e o uso e interpretação de modelos de valor agregado

Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women

Abstract Introduction The association of breast cancer patients’ mortality with estrogen receptor (ER) status (ER + versus ER-) has been well studied. However, little attention has been paid to the relationship between the quantitative measures of ER expression and mortality. Methods We evaluated the association between semi-quantitative, immunohistochemical staining of ER in formalin-fixed paraffin-embedded breast carcinomas and breast cancer-specific mortality risk in an observational cohort of invasive breast cancer in 681 white women and 523 black women ages 35-64 years at first diagnosis of invasive breast cancer, who were followed for a median of 10 years. The quantitative measures of ER examined here included the percentage of tumor cell nuclei positively stained for ER, ER Histo (H)-score, and a score based on an adaptation of an equation presented by Cuzick and colleagues, which combines weighted values of ER H-score, percentage of tumor cell nuclei positively stained for the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results. This is referred to as the ER/PR/HER2 score. Results After controlling for age at diagnosis, race, study site, tumor stage, and histologic grade in multivariable Cox proportional hazards regression models, both percentage of tumor cell nuclei positively stained for ER (P trend = 0.0003) and the ER H-score (P trend = 0.0004) were inversely associated with breast cancer-specific mortality risk. The ER/PR/HER2 score was positively associated with breast cancer-specific mortality risk in women with ER + tumor (P trend = 0.001). Analyses by race revealed that ER positivity was associated with reduced risk of breast cancer-specific mortality in white women and black women. The two quantitative measures for ER alone provided additional discrimination in breast cancer-specific mortality risk only among white women with ER + tumors (both P trend ≤ 0.01) while the ER/PR/HER2 score provided additional discrimination for both white women (P trend = 0.01) and black women (P trend = 0.03) with ER + tumors. Conclusions Our data support quantitative immunohistochemical measures of ER, especially the ER/PR/HER2 score, as a more precise predictor for breast cancer-specific mortality risk than a simple determination of ER positivity

Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study.

BACKGROUND: Early age at first birth and multiparity reduce the risk of estrogen receptor-progesterone receptor (ERPR)-positive breast cancer, whereas breastfeeding reduces the risk of both ERPR-positive and ERPR-negative cancers. METHODS: We used multivariable logistic regression analysis to investigate whether age at first birth ( or =25 years) and breastfeeding (ever/never) modify the long-term effect of parity on risk of ERPR-positive and ERPR-negative cancer using 1,457 incident breast cancer cases and 1,455 controls ages > or =55 years who participated in the Women's Contraceptive and Reproductive Experiences Study. RESULTS: Women who gave birth before age 25 years had a 36% reduced risk of breast cancer compared with nulligravida that was not observed for women who started their families at an older age (P(heterogeneity) = 0.0007). This protective effect was restricted to ERPR-positive breast cancer (P(heterogeneity) = 0.004). Late age at first birth increased the risk of ERPR-negative cancers. Additional births reduced the risk of ERPR-positive cancers among women with an early first birth (P(trend) = 0.0001) and among women who breastfed (P(trend) = 0.004) but not among older mothers or those who never breastfed. In women with a late first birth who never breastfed, multiparity was associated with increased risk of breast cancer. CONCLUSIONS: These findings suggest that the effect of parity on a woman's long-term risk of breast cancer is modified by age at first full-term pregnancy and possibly by breastfeeding

Relationship between migraine history and breast cancer risk among premenopausal and postmenopausal women.

Both migraine and breast cancer are hormonally mediated diseases, and it is biologically plausible that women with a history of migraine may have a reduced breast cancer risk. However, this relationship has only been assessed in a single relatively small study that was unable to assess the effect of migraine triggers, which are also well-established breast cancer risk factors (e.g., use of alcohol and exogenous hormones), on the inverse association observed. Utilizing data on 4,568 breast cancer cases and 4,678 controls who participated in a multicenter population-based case-control study in the United States, we evaluated the association between migraine history and breast cancer risk using unconditional logistic regression. Migraine history data were obtained from structured in-person interviews. Women with a history of migraine had a reduced risk of breast cancer [odds ratio, 0.74; 95% confidence interval (CI), 0.66-0.82]. This risk did not differ by menopausal status, age at migraine diagnosis, use of prescription migraine medications, or when analyses were restricted to women who avoided various migraine triggers (including alcohol, exogenous hormones, and smoking). These data support a previous finding that a history of migraine may be associated with a reduced risk of breast cancer. It extends the prior report in observing that this relationship holds for both premenopausal and postmenopausal women and is independent of exposure to common migraine triggers

CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer.

PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches