Multiple tandem splicing silencer elements suppress aberrant splicing within the long exon 26 of the human Apolipoprotein B gene.

ABSTRACT: BACKGROUND: Apolipoprotein B (APOB) is an integral component of the chylomicron and the atherogenic lipoproteins LDL and Lp(a). Exon 26 of the APOB pre-mRNA is unusually long at 7,572 nt and is constitutively spliced. It is also subject to RNA editing in the intestine, which generates a shortened isoform, APOB48, assembled exclusively into chylomicrons. Due to its length, exon 26 contains multiple pseudo splice sites which are not spliced, but which conform to the degenerate splice site consensus. RESULTS: We demonstrate that these pseudo splice sites are repressed by multiple, tandem splicing silencers distributed along the length of exon 26. The distribution of these elements appears to be heterogeneous, with a greater frequency in the middle 4,800 nt of the exon. CONCLUSION: Repression of these splice sites is key to maintaining the integrity of exon 26 during RNA splicing and therefore the correct expression of both isoforms of APOB

Chaos around Holographic Regge Trajectories

Using methods of Hamiltonian dynamical systems, we show analytically that a dynamical system connected to the classical spinning string solution holographically dual to the principal Regge trajectory is non-integrable. The Regge trajectories themselves form an integrable island in the total phase space of the dynamical system. Our argument applies to any gravity background dual to confining field theories and we verify it explicitly in various supergravity backgrounds: Klebanov-Strassler, Maldacena-Nunez, Witten QCD and the AdS soliton. Having established non-integrability for this general class of supergravity backgrounds, we show explicitly by direct computation of the Poincare sections and the largest Lyapunov exponent, that such strings have chaotic motion.Comment: 28 pages, 5 figures. V3: Minor changes complying to referee's suggestions. Typos correcte

Critical role of the disintegrin metalloprotease ADAM-like Decysin-1 (ADAMDEC1) for intestinal immunity and inflammation

BACKGROUND AND AIMS: ADAM (A Disintegrin And Metalloproteinase) is a family of peptidase proteins, which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like Decysin-1 (ADAMDEC1) a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn's disease patients has provided evidence of a potential role in bowel inflammation. METHODS: Adamdec1(-/-) mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium The clinical response was monitored. RESULTS: The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia. CONCLUSION: In summary, Adamdec1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn's disease

The INCLUDE study: INtegrating and improving Care for patients with infLammatory rheUmatological DisordErs in the community; identifying multimorbidity: Protocol for a pilot randomized controlled trial.

Background: Patients with inflammatory rheumatic conditions such as rheumatoid arthritis, polymyalgia rheumatica and ankylosing spondylitis are at increased risk of common comorbidities such as cardiovascular disease, osteoporosis and anxiety and depression which lead to increased morbidity and mortality. These associated morbidities are often un-recognized and under-treated. While patients with other long-term conditions such as diabetes are invited for routine reviews in primary care, which may include identification and management of co-morbidities, at present this does not occur for patients with inflammatory conditions, and thus, opportunities to diagnose and optimally manage these comorbidities are missed. Objective: To evaluate the feasibility and acceptability of a nurse-led integrated care review (the INtegrating and improving Care for patients with infLammatory rheUmatological DisordErs in the community (INCLUDE) review) for people with inflammatory rheumatological conditions in primary care. Design: A pilot cluster randomized controlled trial will be undertaken to test the feasibility and acceptability of a nurse-led integrated primary care review for identification, assessment and initial management of common comorbidities including cardiovascular disease, osteoporosis and anxiety and depression. A process evaluation will be undertaken using a mixed methods approach including participant self-reported questionnaires, a medical record review, an INCLUDE EMIS template, intervention fidelity checking using audio-recordings of the INCLUDE review consultation and qualitative interviews with patient participants, study nurses and study general practitioners (GPs). Discussion: Success of the pilot study will be measured against the engagement, recruitment and study retention rates of both general practices and participants. Acceptability of the INCLUDE review to patients and practitioners and treatment fidelity will be explored using a parallel process evaluation. Trial Registration: ISRCTN12765345

Challenges and Opportunities: What Can We Learn from Patients Living with Chronic Musculoskeletal Conditions, Health Professionals and Carers about the Concept of Health Literacy Using Qualitative Methods of Inquiry?

The field of health literacy continues to evolve and concern public health researchers and yet remains a largely overlooked concept elsewhere in the healthcare system. We conducted focus group discussions in England UK, about the concept of health literacy with older patients with chronic musculoskeletal conditions (mean age = 73.4 years), carers and health professionals. Our research posed methodological, intellectual and practical challenges. Gaps in conceptualisation and expectations were revealed, reiterating deficiencies in predominant models for understanding health literacy and methodological shortcomings of using focus groups in qualitative research for this topic. Building on this unique insight into what the concept of health literacy meant to participants, we present analysis of our findings on factors perceived to foster and inhibit health literacy and on the issue of responsibility in health literacy. Patients saw health literacy as a result of an inconsistent interactive process and the implications as wide ranging; healthcare professionals had more heterogeneous views. All focus group discussants agreed that health literacy most benefited from good inter-personal communication and partnership. By proposing a needs-based approach to health literacy we offer an alternative way of conceptualising health literacy to help improve the health of older people with chronic conditions

Developing a community based psychosocial intervention with older people and third sector workers for anxiety and depression: a qualitative study

Background: One-in-five people in the UK experience anxiety and/or depression in later life. However, anxiety and depression remain poorly detected in older people, particularly in those with chronic physical ill health. In the UK, a stepped care approach, to manage common mental health problems, is advocated which includes service provision from non-statutory organisations (including third/voluntary sector). However, evidence to support such provision, including the most effective interventions, is limited. The qualitative study reported here constitutes the first phase of a feasibility study which aims to assess whether third sector workers can deliver a psychosocial intervention to older people with anxiety and/or depression. The aim of this qualitative study is to explore the views of older people and third sector workers about anxiety and depression among older people in order to refine an intervention to be delivered by third sector workers. Methods: Semi-structured interviews with participants recruited through purposive sampling from third sector groups in North Staffordshire. Interviews were digitally recorded with consent, transcribed and analysed using principles of constant comparison. Results: Nineteen older people and 9 third sector workers were interviewed. Key themes included: multiple forms of loss, mental health as a personal burden to bear, having courage and providing/receiving encouragement, self- worth and the value of group activities, and tensions in existing service provision, including barriers and gaps. Conclusions: The experience of loss was seen as central to feelings of anxiety and depression among community- dwelling older people. This study contributes to the evidence pointing to the scale and severity of mental health needs for some older people which can arise from multiple forms of loss, and which present a significant challenge to health, social care and third sector services. The findings informed development of a psychosocial intervention and training for third sector workers to deliver the intervention

An Integrative Design Framework for New Service Development

Service innovation is focused on customer value creation. At its core, customer-centric service innovation in an increasingly digital world is technology-enabled, human-centered, and process-oriented. This requires a cross-disciplinary, holistic approach to new service design and development (NSD). This paper proposes a new service strategy-aligned integrative design framework for NSD. It correlates the underlying theories and principles of disparate but interrelated aspects of service design thinking: service strategy, concept, design, experience and architecture into a coherent framework for NSD, consistent with the service brand value. Application of the framework to NSD is envisioned to be iterative and holistic, accentuated on continuous organizational and customer learning. The preliminary framework's efficacy is illustrated using a simplified telecom case example. © Springer International Publishing Switzerland 2014

Profiling strugglers in a graduate-entry medicine course at Nottingham: a retrospective case study

Background 10-15% of students struggle at some point in their medicine course. Risk factors include weaker academic qualifications, male gender, mental illness, UK ethnic minority status, and poor study skills. Recent research on an undergraduate medicine course provided a toolkit to aid early identification of students likely to struggle, who can be targeted by established support and study interventions. The present study sought to extend this work by investigating the number and characteristics of strugglers on a graduate-entry medicine (GEM) programme. Methods A retrospective study of four GEM entry cohorts (2003–6) was carried out. All students who had demonstrated unsatisfactory progress or left prematurely were included. Any information about academic, administrative, personal, or social difficulties, were extracted from their course progress files into a customised database and examined. Results 362 students were admitted to the course, and 53 (14.6%) were identified for the study, of whom 15 (4.1%) did not complete the course. Students in the study group differed from the others in having a higher proportion of 2ii first degrees, and scoring less well on GAMSAT, an aptitude test used for admission. Within the study group, it proved possible to categorise students into the same groups previously reported (struggler throughout, pre-clinical struggler, clinical struggler, health-related struggler, borderline struggler) and to identify the majority using a number of flags for early difficulties. These flags included: missed attendance, unsatisfactory attitude or behaviour, health problems, social/family problems, failure to complete immunity status checks, and attendance at academic progress committee. Conclusions Problems encountered in a graduate-entry medicine course were comparable to those reported in a corresponding undergraduate programme. A toolkit of academic and non-academic flags of difficulty can be used for early identification of many who will struggle, and could be used to target appropriate support and interventions

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table