Evolution of candidate transcriptional regulatory motifs since the human-chimpanzee divergence.

BACKGROUND: Despite the recent completion of the chimpanzee genome project, few functionally significant sequence differences between humans and chimpanzees have thus far been identified. Alteration in transcriptional regulatory mechanisms represents an important platform for evolutionary change, suggesting that a significant proportion of functional human-chimpanzee sequence differences may affect regulatory elements. RESULTS: To explore this hypothesis, we performed genome-wide identification of conserved candidate transcription-factor binding sites that have evolved since the divergence of humans and chimpanzees. Analysis of candidate transcription-factor binding sites conserved between mouse and chimpanzee yet absent in human indicated that loss of candidate transcription-factor binding sites in the human lineage was not random but instead correlated with the biologic functions of associated genes. CONCLUSION: Our data support the notion that changes in transcriptional regulation have contributed to the recent evolution of humans. Moreover, genes associated with mutated candidate transcription-factor binding sites highlight potential pathways underlying human-chimpanzee divergence.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Learning about the complexity of humanised care: findings from a longitudinal study of nurse students’ perceptions

Background, including underpinning literature and, wherever possible, the international relevance of the research The rise in elderly populations with complex long-term conditions is a global phenomenon (World Health Organisation, 2011). However evidence has emerged internationally around concerns about quality of care, particularly for older people (Katz 2011; Organisation for Economic Cooperation and Development, 2013). It has been argued that in target-driven care environments, there is the potential for care professionals to lose sight of the person receiving the care and focuses on task-completion, resulting in dehumanising care cultures (Galvin and Todres 2013). Educating nurse students to effectively as well as compassionately deliver complex care to vulnerable people represents considerable challenges. Following a number of high profile examples of poor quality care in the United Kingdom (UK) (Francis 2013), health profession education providers now follow professional body guidelines that mandate that values for compassionate practice clearly underpin curricula. Limited evidence exists however, concerning the impact of this initiative over time. This paper reports on a study that evidences the impact on students of an education programme based on a humanising care philosophy in shaping the students’ value base as they progress through their education programmes. Aim(s) and/or research question(s)/research hypothesis(es) . This paper reports on a five-phase longitudinal study exploring the impact of an undergraduate-nursing curriculum based on a humanising care philosophy on the values of individual students. Research methodology/research design, any ethical issues, and methods of data collection and analysis The study uses a qualitative longitudinal approach to understanding the beliefs and values of student nurses from the day of entry, through their education programme to completion. Focusing on two cohorts of students one year apart, data were collected by individual interview at commencement and completion and by focus groups at the end of their first placement and at the end of their first and second years. This presentation reports up to the end of the programme for the first cohort and end of second year for the second cohort. Ethics approval was gained for the entire project. At each stage of the process, students were formally invited to participate and on-going individual consent was gained. The audio-recordings were transcribed verbatim and analysed thematically. Key findings and recommendations By the end of their first placement, both groups were very similar in the expression of their values and to some extent presented a rather negative view of their experiences. However students from both groups became more articulate in expressing their values particularly in relation to their placement experience, as they moved through their programme. Four on-going and developing themes emerged from the data: personal journey, impact of the curriculum, impact of practice and values development. Overall, although each cohort followed two distinct curricula, there were few differences between the groups at each stage. Reasons for this will be discussed. Both groups felt they had become less judgmental, that the curriculum had empowered them to challenge practice and enhanced their confidence. Students also reported that their mentors (placement supervisors) role modelled authentic compassionate care in practice. Over time students’ insight into the complexity of caring developed and their understanding of the importance of practice that respected patient individuality deepened. This study has evidenced the strong link between curriculum and its impact on the evolving values of nursing students. Whilst this paper reports on a local study from one university in the UK, transferability of findings to other settings can be judged; it is argued that the insights will have resonance for nurse educators more widely as well as other health professional disciplines. References Commissioning Board Chief Nursing Officer and Department of Health Chief Nurse Advisor (2012). Compassion in Practice: Nursing, Midwifery and Care Staff. Our vision and strategy. Retrieved 22nd January 2016 from: http://www.england.nhs.uk/wp-content/uploads/2012/12/compassion-in-practice.pdf Francis Inquiry, (2013). Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry: Executive summary. Crown Copyright: London. Galvin, K., Todres, L. (2013). Caring and Well-Being: A Lifeworld Approach. Routledge: Abingdon, Oxon. Katz, P.R. (2011). An International Perspective on Long Term Care: Focus on Nursing Homes. Journal of American Medical Directors Association. 12 (7): 487-492 OECD (2013) OECD Reviews of Health Care Quality: Denmark. Retrieved 7th Retrieved 22nd January 2016 from: http://www.oecd.org/els/health-systems/ReviewofHealthCareQualityDENMARK_ExecutiveSummary.pdf WHO (2011) Global Health and Ageing. Retrieved 22nd January 2016 from: http://www.who.int/ageing/publications/global_health.pdf Key words: (5) • Nurse education • Professional values • Humanising care • Curriculum • Longitudinal qualitative research 3 key points to indicate how your work contributes to knowledge development within the selected theme • Nursing students were able to clearly articulate values that underpin humanised care • This study provides evidence for the strong link between curriculum and its impact on the evolving values of nursing students • The curriculum is one factor in embedding humanised values in nursing students; further research is required

TALE and NF-Y co-occupancy marks enhancers of developmental control genes during zygotic genome activation in zebrafish [preprint]

Animal embryogenesis is initiated by maternal factors, but zygotic genome activation (ZGA) shifts control to the embryo at early blastula stages. ZGA is thought to be mediated by specialized maternally deposited transcription factors (TFs), but here we demonstrate that NF-Y and TALE – TFs with known later roles in embryogenesis – co-occupy unique genomic elements at zebrafish ZGA. We show that these elements are selectively associated with early-expressed genes involved in transcriptional regulation and possess enhancer activity in vivo. In contrast, we find that elements individually occupied by either NF-Y or TALE are associated with genes acting later in development – such that NF-Y controls a cilia gene expression program while TALE TFs control expression of hox genes. We conclude that NF-Y and TALE have a shared role at ZGA, but separate roles later during development, demonstrating that combinations of known TFs can regulate subsets of key developmental genes at vertebrate ZGA

A 100 kHz time-resolved multiple-probe femtosecond to second infrared absorption spectrometer

We present a dual-amplifier laser system for time-resolved multiple-probe infrared (IR) spectroscopy based on the ytterbium potassium gadolinium tungstate (Yb:KGW) laser medium. Comparisons are made between the ytterbium-based technology and titanium sapphire laser systems for time-resolved IR spectroscopy measurements. The 100 kHz probing system provides new capability in time-resolved multiple-probe experiments, as more information is obtained from samples in a single experiment through multiple-probing. This method uses the high repetition-rate probe pulses to repeatedly measure spectra at 10 μs intervals following excitation allowing extended timescales to be measured routinely along with ultrafast data. Results are presented showing the measurement of molecular dynamics over >10 orders of magnitude in timescale, out to 20 ms, with an experimental time response o

Equitability revisited: why the “equitable threat score” is not equitable

In the forecasting of binary events, verification measures that are “equitable” were defined by Gandin and Murphy to satisfy two requirements: 1) they award all random forecasting systems, including those that always issue the same forecast, the same expected score (typically zero), and 2) they are expressible as the linear weighted sum of the elements of the contingency table, where the weights are independent of the entries in the table, apart from the base rate. The authors demonstrate that the widely used “equitable threat score” (ETS), as well as numerous others, satisfies neither of these requirements and only satisfies the first requirement in the limit of an infinite sample size. Such measures are referred to as “asymptotically equitable.” In the case of ETS, the expected score of a random forecasting system is always positive and only falls below 0.01 when the number of samples is greater than around 30. Two other asymptotically equitable measures are the odds ratio skill score and the symmetric extreme dependency score, which are more strongly inequitable than ETS, particularly for rare events; for example, when the base rate is 2% and the sample size is 1000, random but unbiased forecasting systems yield an expected score of around −0.5, reducing in magnitude to −0.01 or smaller only for sample sizes exceeding 25 000. This presents a problem since these nonlinear measures have other desirable properties, in particular being reliable indicators of skill for rare events (provided that the sample size is large enough). A potential way to reconcile these properties with equitability is to recognize that Gandin and Murphy’s two requirements are independent, and the second can be safely discarded without losing the key advantages of equitability that are embodied in the first. This enables inequitable and asymptotically equitable measures to be scaled to make them equitable, while retaining their nonlinearity and other properties such as being reliable indicators of skill for rare events. It also opens up the possibility of designing new equitable verification measures

Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes

Background: Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings. Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action.Methods: Two doses of ZnONP (50 and 150 cm(2)/rat) were intratracheally instilled into the lungs of rats with assessments made at 24 h, 1 wk, and 4 wks after instillation to evaluate dose- and time-course responses. Assessments included bronchoalveolar lavage (BAL) fluid analysis, histological analysis, transmission electron microscopy, and IgE and IgA measurement in the serum and BAL fluid. To evaluate the mechanism, alternative ZnONP, ZnONP-free bronchoalveolar lavage exudate, and dissolved Zn2+ (92.5 mu g/rat) were also instilled to rats. Acridine orange staining was utilized in macrophages in culture to evaluate the lysosomal membrane destabilization by NP.Results: ZnONP induced eosinophilia, proliferation of airway epithelial cells, goblet cell hyperplasia, and pulmonary fibrosis. Bronchocentric interstitial pulmonary fibrosis at the chronic phase was associated with increased myofibroblast accumulation and transforming growth factor-beta positivity. Serum IgE levels were up-regulated by ZnONP along with the eosinophilia whilst serum IgA levels were down-regulated by ZnONP. ZnONP are rapidly dissolved under acidic conditions (pH 4.5) whilst they remained intact around neutrality (pH 7.4). The instillation of dissolved Zn2+ into rat lungs showed similar pathologies (eg., eosinophilia, bronchocentric interstitial fibrosis) as were elicited by ZnONP. Lysosomal stability was decreased and cell death resulted following treatment of macrophages with ZnONP in vitro.Conclusions: We hypothesise that rapid, pH-dependent dissolution of ZnONP inside of phagosomes is the main cause of ZnONP-induced diverse progressive severe lung injuries

Economics methods in Cochrane systematic reviews of health promotion and public health related interventions.

Peer reviewedPublisher PD

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system