Multiple mRNA isoforms of the transcription activator protein CREB

We have characterized cDNA clones representing mouse CREB (cyclic AMP responsive element binding protein) mRNA isoforms. These include CREBA and CREBa, of which the rat and human homologues have been previously identified. Both encode proteins with CREbinding activity and identical transactivation potential. The additional CREB mRNA isoforms potentially encode CREB related proteins. From the structural organization of the mouse CREB gene we conclude that the multiple transcripts are generated by alternative splicing. Furthermore we show that specific CREB mRNA isoforms are expressed at a high level in the adult testis. Expression of these isoforms is induced after commencement of spermatogenesis. In situ hybridization suggests that this expression occurs predominantly in the primary spermatocytes. Comparison of the CREB gene with the recently isolated CREM (cAMP responsive element modulator) cDNAs illustrates that the two genes have arisen by gene duplication and have diverged to encode transcriptional activators and repressors of the cAMP signal transduction pathway

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.

The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage

Liver transplantation for alcoholic cirrhosis: Long term follow-up and impact of disease recurrence

Background. Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. Methods. Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. Results. In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were over-represented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. Conclusions. Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease

Speculative Method and Twitter: Bots, Energy and Three Conceptual Characters

This paper aims to contribute to recent innovations in social scientific methodology that aspire to address the complex, iterative and performative dimensions of method. In particular, we focus on the becoming-with character of social events, and propose a speculative method for engaging with the not-as-yet. This work, being part of a larger project that uses Speculative Design and ethnographic methods to explore energy-demand reduction, specifically considers the ways in which energy-demand reduction features in the Twitter-sphere. Developing and deploying three automated Bots whose function and communications are at best obscure, and not uncommonly nonsensical, we trace some of ways in which they intervene and provoke. Heuristically, we draw on the ‘conceptual characters’ of idiot, parasite and diplomat in order to grasp how the Bots act within Twitter to evoke the instability and emergent eventuations of energy-demand reduction, community and related practices. We conclude by drawing out some of the wider implications of this particular enactment of speculative method

The Indiana Learning Health System Initiative: Early experience developing a collaborative, regional learning health system

Introduction Learning health systems (LHSs) are usually created and maintained by single institutions or healthcare systems. The Indiana Learning Health System Initiative (ILHSI) is a new multi-institutional, collaborative regional LHS initiative led by the Regenstrief Institute (RI) and developed in partnership with five additional organizations: two Indiana-based health systems, two schools at Indiana University, and our state-wide health information exchange. We report our experiences and lessons learned during the initial 2-year phase of developing and implementing the ILHSI. Methods The initial goals of the ILHSI were to instantiate the concept, establish partnerships, and perform LHS pilot projects to inform expansion. We established shared governance and technical capabilities, conducted a literature review-based and regional environmental scan, and convened key stakeholders to iteratively identify focus areas, and select and implement six initial joint projects. Results The ILHSI successfully collaborated with its partner organizations to establish a foundational governance structure, set goals and strategies, and prioritize projects and training activities. We developed and deployed strategies to effectively use health system and regional HIE infrastructure and minimize information silos, a frequent challenge for multi-organizational LHSs. Successful projects were diverse and included deploying a Fast Healthcare Interoperability Standards (FHIR)-based tool across emergency departments state-wide, analyzing free-text elements of cross-hospital surveys, and developing models to provide clinical decision support based on clinical and social determinants of health. We also experienced organizational challenges, including changes in key leadership personnel and varying levels of engagement with health system partners, which impacted initial ILHSI efforts and structures. Reflecting on these early experiences, we identified lessons learned and next steps. Conclusions Multi-organizational LHSs can be challenging to develop but present the opportunity to leverage learning across multiple organizations and systems to benefit the general population. Attention to governance decisions, shared goal setting and monitoring, and careful selection of projects are important for early success

Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570G>T in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity

Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes

Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, B and C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these \u27hotspot\u27 sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer

A study of indoor carbon dioxide levels and sick leave among office workers

BACKGROUND: A previous observational study detected a strong positive relationship between sick leave absences and carbon dioxide (CO(2)) concentrations in office buildings in the Boston area. The authors speculated that the observed association was due to a causal effect associated with low dilution ventilation, perhaps increased airborne transmission of respiratory infections. This study was undertaken to explore this association. METHODS: We conducted an intervention study of indoor CO(2) levels and sick leave among hourly office workers employed by a large corporation. Outdoor air supply rates were adjusted periodically to increase the range of CO(2) concentrations. We recorded indoor CO(2) concentrations every 10 minutes and calculated a CO(2) concentration differential as a measure of outdoor air supply per person by subtracting the 1–3 a.m. average CO(2) concentration from the same-day 9 a.m. – 5 a.m. average concentration. The metric of CO(2) differential was used as a surrogate for the concentration of exhaled breath and for potential exposure to human source airborne respiratory pathogens. RESULTS: The weekly mean, workday, CO(2) concentration differential ranged from 37 to 250 ppm with a peak CO(2) concentration above background of 312 ppm as compared with the American Society of Heating, Refrigeration and Air-conditioning Engineers (ASHRAE) recommended maximum differential of 700 ppm. We determined the frequency of sick leave among 294 hourly workers scheduled to work approximately 49,804.2 days in the study areas using company records. We found no association between sick leave and CO(2) differential CONCLUSIONS: The CO(2) differential was in the range of very low values, as compared with the ASHRAE recommended maximum differential of 700 ppm. Although no effect was found, this study was unable to test whether higher CO(2) differentials may be associated with increased sick leave

Mining Big Data for Tourist Hot Spots: Geographical Patterns of Online Footprints

Understanding the complex, and often unequal, spatiality of tourist demand in urban contexts requires other methodologies, among which the information base available online and in social networks has gained prominence. Innovation supported by Information and Communication Technologies in terms of data access and data exchange has emerged as a complementary supporting tool for the more traditional data collection techniques currently in use, particularly, in urban destinations where there is the need to more (near)real-time monitoring. The capacity to collect and analise massive amounts of data on individual and group behaviour is leading to new data-rich research approaches. This chapter addresses the potential for discovering geographical insights regarding tourists’ spatial patterns within a destination, based on the analysis of geotagged data available from two social networks. ·info:eu-repo/semantics/publishedVersio