The Role of DNA Methylation in Regulation of the Murine Lhx3 Gene

LHX3 is a LIM-homeodomain transcription factor with critical roles in pituitary and nervous system development. Mutations in the LHX3 gene are associated with pediatric diseases featuring severe hormone deficiencies, hearing loss, developmental delay, and other symptoms. The mechanisms that govern LHX3/Lhx3 transcription are poorly understood. In this study, we examined the role of DNA methylation in the expression status of the mouse Lhx3 gene. Pituitary cells that do not normally express Lhx3 (Pit-1/0 cells) were treated with 5-aza-2’-deoxycytidine, a demethylating reagent. This treatment lead to activation of Lhx3 gene expression suggesting that methylation contributes to Lhx3 regulation. Treatment of Pit-1/0 pituitary cells with a combination of a demethylating reagent and a histone deacetylase inhibitor led to rapid activation of Lhx3 expression, suggesting possible crosstalk between DNA methylation and histone modification processes. To assess DNA methylation levels, treated and untreated Pit-1/0 genomic DNA was subjected to bisulfite conversion and sequencing. Treated Pit-1/0 cells had decreased methylation at specific sites in the Lhx3 locus compared to untreated cells. Chromatin immunoprecipitation assays demonstrated interactions between the MeCp2 methyl binding protein and Lhx3 promoter regions in the Pit-1/0 cell line. Overall, this study demonstrates that DNA methylation patterns of the Lhx3 gene are associated with its expression status

A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency

Background/Aims: Recessive mutations in the LHX3 homeodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3. Methods: Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized. Results: A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the a-glycoprotein and PRL target genes. Conclusion: The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene. copyright (C) 2012 S. Karger AG, Base

Effective Theories for Circuits and Automata

Abstracting an effective theory from a complicated process is central to the study of complexity. Even when the underlying mechanisms are understood, or at least measurable, the presence of dissipation and irreversibility in biological, computational and social systems makes the problem harder. Here we demonstrate the construction of effective theories in the presence of both irreversibility and noise, in a dynamical model with underlying feedback. We use the Krohn-Rhodes theorem to show how the composition of underlying mechanisms can lead to innovations in the emergent effective theory. We show how dissipation and irreversibility fundamentally limit the lifetimes of these emergent structures, even though, on short timescales, the group properties may be enriched compared to their noiseless counterparts.Comment: 11 pages, 9 figure

Uso de la espectrometría de masas de relaciones isotópicas como técnica emergente en el análisis de aceites vegetales

As the practice of vegetable oil adulteration becomes more sophisticated, the possibility to subvert detection using established techniques such as capillary gas chromatography is increasing. One of the most powerful techniques to be used in food authenticity studies is stable isotope ratio mass spectrometry (SIRMS) which utilises differences in the natural abundance of the stable isotopes of the ‘light’ bio-elements hydrogen, nitrogen, carbon, oxygen and sulfur to detect food fraud. SIRMS has found application in the authentication of a wide range of foodstuffs, including fruit juices, wines, spirits, honey and to detect the adulteration of flavour compounds with synthetic analogues. This papers reviews the current state-of-the-art for the authentication of vegetable oils using SIRMS and highlights emergent techniques such as compound- and position specific-isotope mass spectrometry. These latter developments offer the potential to provide more rapid and improved detection of the economic adulteration of vegetable oils.A medida que la práctica de la adulteración de aceites vegetales se hace más sofisticada, las posibilidades de evitar la detección utilizando técnicas tradicionales como la cromatografía de gases en columna capilar aumentan. Una de las técnicas más poderosas que más se utilizan en los estudios de autentificación de alimentos es la espectrometría de masas de relaciones isotópicas, que utiliza diferencias en la abundancia natural de isótopos estables de elementos ligeros biológicos hidrógeno, nitrógeno, carbón, oxigeno y azufre para detectar fraude en los alimentos. La espectrometría de masas de relaciones isotópicas ha encontrado aplicación en la autentificación de una amplia gama de alimentos, incluyendo zumos de frutas, vinos, bebidas alcohólicas de alta graduación, miel, y en la detección de la adulteración de los compuestos aromáticos con sus análogos de origen sintético. Este trabajo revisa el estado actual de los conocimientos de autentificación de aceites vegetales utilizando la espectrometría de masas de relaciones isotópicas y las aportaciones de tecnologías emergentes tales como la espectrometría de masas de compuestos isotópicos. Estos últimos desarrollos ofrecen la posibilidad de suministrar una detección más rápida y mejorada de la adulteración de aceites vegetales

The Epidemiology of Multimorbidity in Primary Care

Background: Multimorbidity places a substantial burden on patients and the healthcare system but few contemporary data are available. Aim: To describe the epidemiology of multimorbidity in adults in England and quantify associations between multimorbidity and health service utilisation. Design: Retrospective cohort study Setting: A random sample of 403,985 adult patients (≥18 years) in England who were registered with a general practice on 1 January 2012 and included in the Clinical Practice Research Datalink. Methods: We defined multimorbidity as having two or more of 36 long-term conditions recorded in patients’ medical records and quantified associations between multimorbidity and health service utilisation (GP consultations, prescriptions, and hospitalisations) over four years. Results: 27.2% of patients were multimorbid. The most prevalent conditions were hypertension (18.2%), depression or anxiety (10.3%), and chronic pain (10.1%). Prevalence of multimorbidity was higher in females than males (30% vs. 24.4% respectively) and among those with lower socioeconomic status (33.8% in the most deprived quintile vs. 24.2% in the least deprived quintile). Physical-mental comorbidity contributed a much greater proportion of overall morbidity in both younger patients and those patients with lower socioeconomic status. Multimorbidity was strongly associated with health service utilisation. Multimorbid patients accounted for 53% of GP consultations, 79% of prescriptions, and 56% percent of hospital admissions. Conclusion: Multimorbidity is common, socially patterned, and associated with increased health service utilisation. These findings support the need to improve the quality and efficiency of health services providing care to multimorbid patients at the practice and national-level.This study received no specific funding. Kirsty Rhodes was supported by the UK Medical Research Council (grant number: U105260558)

Primary Care Appointment Availability for Medicaid Patients: Comparing Traditional and Premium Assistance Plans

Key Findings: In 2014, Arkansas and Iowa expanded their Medicaid programs and enrolled many of their adult beneficiaries in commercial Marketplace plans. This study suggests that this “private option” may make it easier for new Medicaid patients to get primary care appointments

From algebra to logic: there and back again -- the story of a hierarchy

This is an extended survey of the results concerning a hierarchy of languages that is tightly connected with the quantifier alternation hierarchy within the two-variable fragment of first order logic of the linear order.Comment: Developments in Language Theory 2014, Ekaterinburg : Russian Federation (2014