Structural Biology of Human H3K9 Methyltransferases

SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity. Enhanced version: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available i

Healthcare professionals’ views on patient-centered care in hospitals

Background: Patient-centered care (PCC) is a main determinant of care quality. Research has shown that PCC is a multi-dimensional concept, and organizations that provide PCC well report better patient and organizational outcomes. However, little is known about the relative importance of PCC dimensions. The aim of this study was therefore to investigate the relative importance of the eight dimensions of PCC according to hospital-based healthcare professionals, and examine whether their viewpoints are determined by context. Methods: Thirty-four healthcare professionals (16 from the geriatrics department, 15 from a surgical intensive care unit, 3 quality employees) working at a large teaching hospital in New York City were interviewed using Q methodology. Participants were asked to rank 35 statements representing eight dimensions of PCC extracted from the literature: patient preferences, physical comfort, coordination of care, emotional support, acce

Further progress in the study of epsilon iron oxide in archaeological baked clays

The occurrence of ε-Fe2O3 in archaeological samples that have been subjected to high temperatures is gradually being detected by the use of micrometric structural characterization techniques. This work provides new information by revealing that the ε-Fe2O3 is formed as a response to temperature, the aggregation state and the position within the baked clay with respect to the nearest heat source. In addition, depending mainly on the atmospheric environment, the temperature reached by the combustion structure, the distance from the heating source and the particle aggregation, other iron oxide magnetic phases are produced. In the baked clay studied here, hematite is found over the whole range of samples studied but its magnetic contribution is negligible. Magnetite is observed at the sample surface, probably due to local atmospheric environment closest to the combustion source. Maghemite is found at all depths up to 6 cm below the sample surface. ε-Fe2O3 has a limited distribution, found within 2–3 cm of the sample surface. Furthermore, the viability of this compound as a palaeofield marker has been evaluated in both archaeological and synthetic samples. The results indicate that ε-Fe2O3 is able to register the direction of the magnetic field. Linear palaeointensity plots have been obtained in synthetic samples, although the value of the palaeofield could be, sometimes, overestimated

Performance of Survivin mRNA as a Biomarker for Bladder Cancer in the Prospective Study UroScreen

BACKGROUND: Urinary biomarkers have the potential to improve the early detection of bladder cancer. Most of the various known markers, however, have only been evaluated in studies with cross-sectional design. For proper validation a longitudinal design would be preferable. We used the prospective study UroScreen to evaluate survivin, a potential biomarker that has multiple functions in carcinogenesis. METHODS/RESULTS: Survivin was analyzed in 5,716 urine samples from 1,540 chemical workers previously exposed to aromatic amines. The workers participated in a surveillance program with yearly examinations between 2003 and 2010. RNA was extracted from urinary cells and survivin was determined by Real-Time PCR. During the study, 19 bladder tumors were detected. Multivariate generalized estimation equation (GEE) models showed that β-actin, representing RNA yield and quality, had the strongest influence on survivin positivity. Inflammation, hematuria and smoking did not confound the results. Survivin had a sensitivity of 21.1% for all and 36.4% for high-grade tumors. Specificity was 97.5%, the positive predictive value (PPV) 9.5%, and the negative predictive value (NPV) 99.0%. CONCLUSIONS: In this prospective and so far largest study on survivin, the marker showed a good NPV and specificity but a low PPV and sensitivity. This was partly due to the low number of cases, which limits the validity of the results. Compliance, urine quality, problems with the assay, and mRNA stability influenced the performance of survivin. However, most issues could be addressed with a more reliable assay in the future. One important finding is that survivin was not influenced by confounders like inflammation and exhibited a relatively low number of false-positives. Therefore, despite the low sensitivity, survivin may still be considered as a component of a multimarker panel

The Impact of Error-Management Climate, Error Type and Error Originator on Auditors’ Reporting Errors Discovered on Audit Work Papers

We examine factors affecting the auditor’s willingness to report their own or their peers’ self-discovered errors in working papers subsequent to detailed working paper review. Prior research has shown that errors in working papers are detected in the review process; however, such detection rates only rarely exceed 50% of the seeded errors. Hence, measures that encourage auditors to be alert to their own (or their peers’) potential errors any time they revisit the audit working papers may be valuable in detecting such residual errors and potentially correcting them before damage occurs to the audit firm or its client. We hypothesize that three factors affect the auditor’s willingness to report post detailed review discovered errors: the local office error-management climate (open versus blame), the type of error (mechanical versus conceptual) and who committed the error (the individual who committed the error (self) or a peer). Local office error-management climate is said to be open and supportive where errors and mistakes are accepted as part of everyday life as long as they are learned from and not repeated. In alternative, a blame error-management climate focuses on a “get it right the first time” culture where mistakes are not tolerated and blame gets attached to those admitting to or found committing such errors. We find that error-management climate has a significant overall effect on auditor willingness to report errors, as does who committed the error originally. We find both predicted and unpredicted significant interactions among the three factors that qualify these observed significant main effects. We discuss implications for audit practice and further research

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

Is “disease management” the answer to our problems? No! Population health management and (disease) prevention require “management of overall well-being”

BACKGROUND: Disease management programs based on the chronic care model have achieved successful and long-term improvement in the quality of chronic care delivery and patients’ health behaviors and physical quality of life. However, such programs have not been able to maintain or improve broader self-management abilities or social well-being, which decline over time in chronically ill patients. Disease management efforts, population health management initiatives and innovative primary care solutions are still mainly focused on clinical and functional outcomes and health behaviors (e.g., smoking cessation, exercise, and diet) failing to address individuals’ overall quality of life and well-being. Individuals’ ability to achieve well-being can be assessed with great specificity through the application of social production function (SPF) theory. This theory asserts that people produce their own well-being by trying to optimize the achievement of instrumental goals (stimulation, comfort, status, behavioral confirmation, affection) that provide the means to achieve the larger, universal goals of physical and social well-being. DISCUSSION: A shift in focus from the management of physical function, disease limitations, and lifestyle behaviors alone to an approach that fosters self-management abilities such as self-efficacy and resource investment as well as overall quality of life, is urgently needed. Disease management interventions should be aimed at adequately addressing all difficulties chronically ill patients face in life, such as the effects of pain and fatigue on the ability to maintain a job and social life and to participate in activities promoting physical and social well-being. Patients’ ability to maintain engagement in stimulating work and social activities with the people who are important to them may be even more important than aspects of disease self-management such as blood pressure or glycemic control. Interventions should aim to make chronically ill patients capable of managing their own well-being and adequately addressing their needs in a broader sense. SUMMARY: So, is disease management the answer to our problems in the time of aging populations and increased prevalence of unhealthy lifestyles, chronic illnesses, and comorbidity? No! Effective (disease) prevention, disease management, patient-centered care, and high-quality chronic care and/or population health management calls for management of overall well-being

The gap between policy and practice: a systematic review of patient-centred care interventions in chronic heart failure

Patient-centred care (PCC) is recommended in policy documents for chronic heart failure (CHF) service provision, yet it lacks an agreed definition. A systematic review was conducted to identify PCC interventions in CHF and to describe the PCC domains and outcomes. Medline, Embase, CINAHL, PsycINFO, ASSIA, the Cochrane database, clinicaltrials.gov, key journals and citations were searched for original studies on patients with CHF staged II–IV using the New York Heart Association (NYHA) classification. Included interventions actively supported patients to play informed, active roles in decision-making about their goals of care. Search terms included ‘patient-centred care’, ‘quality of life’ and ‘shared decision making’. Of 13,944 screened citations, 15 articles regarding 10 studies were included involving 2540 CHF patients. Three studies were randomised controlled trials, and seven were non-randomised studies. PCC interventions focused on collaborative goal setting between patients and healthcare professionals regarding immediate clinical choices and future care. Core domains included healthcare professional-patient collaboration, identification of patient preferences, patient-identified goals and patient motivation. While the strength of evidence is poor, PCC has been shown to reduce symptom burden, improve health-related quality of life, reduce readmission rates and enhance patient engagement for patients with CHF. There is a small but growing body of evidence, which demonstrates the benefits of a PCC approach to care for CHF patients. Research is needed to identify the key components of effective PCC interventions before being able to deliver on policy recommendations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10741-015-9508-5) contains supplementary material, which is available to authorized users