The effect of interleukin-10 and transforming growth factor beta-1 on HLA-DR expression in colonic epithelial cells.

The aim of this study was to assess whether interleukin-10 (IL-10) and/or transforming growth factor beta-1 (TGFbeta1) downregulate HLA-DR expression using the HT29 cell line as a model of colonic epithelial cells. HLA-DR expression was induced in HT29 cells with gamma-interferon. The effects of IL-10 alone, TGFbeta1 alone, and IL-10 and TGFbeta1 in combination were studied. HLA-DR expression was assessed using flow cytometric analysis. Gamma-interferon induced HLA-DR expression in a dose-dependent fashion. In the absence of gamma-interferon, neither IL-10 nor TGFbeta1 induced HLA-DR expression. In isolation, neither IL-10 nor TGFbeta1 downregulated HLA-DR expression. When IL-10 and TGFbeta1 were added in combination, small (6-30%) statistically significant reductions in HLA-DR expression were seen. The biological significance is unclear

Variational inference for computational imaging inverse problems

Machine learning methods for computational imaging require uncertainty estimation to be reliable in real settings. While Bayesian models offer a computationally tractable way of recovering uncertainty, they need large data volumes to be trained, which in imaging applications implicates prohibitively expensive collections with specific imaging instruments. This paper introduces a novel framework to train variational inference for inverse problems exploiting in combination few experimentally collected data, domain expertise and existing image data sets. In such a way, Bayesian machine learning models can solve imaging inverse problems with minimal data collection efforts. Extensive simulated experiments show the advantages of the proposed framework. The approach is then applied to two real experimental optics settings: holographic image reconstruction and imaging through highly scattering media. In both settings, state of the art reconstructions are achieved with little collection of training data

Hacking Education in a Digital Age: teacher education, curriculum and literacies

n this collection, the authors put forth different philosophical conceptions of "hacking education" in response to the educational, societal, and technological demands of the 21st century. Teacher Educators are encouraged to draw on the collection to rethink how "hacking education" can be understood simultaneously as a "praxis" informed by desires for malice, as well as a creative site for us to reconsider the possibilities and limitations of teaching and learning in a digital era. How do we hack beyond the limits of circumscribed experiences, regulated subjective encounters with knowledge and the limits imposed by an ever constrained 21st century schooling system in the hopes of imagining better and more meaningful futures? How do we foster ingenuity and learning as the end itself (and not learning as economic imperative) in a world where technology, in part, positions individuals as zombie-like and as an economic end in itself? Can we "hack" education in such a way that helps to mitigate the black hat hacking that increasingly lays ruin to individual lives, government agencies, and places of work? How can we, as educators, facilitate the curricular and pedagogical processes of reclaiming the term hacking so as to remember and remind ourselves that hacking's humble roots are ultimately pedagogical in its very essence? As a collection of theoretical and pedagogical pieces, the chapters in the collection are of value to both scholars and practitioners who share the same passion and commitment to changing, challenging and reimagining the script that all too often constrains and prescribes particular visions of education. Those who seek to question the nature of teaching and learning and who seek to develop a richer theoretical vocabulary will benefit from the insightful and rich collection of essays presented in this collection. In this regard, the collection offers something for all who might wish to rethink the fundamental dynamics of education or, as Morpheus asks of Neo in The Matrix, bend the rules of conventional ways of knowing and being

Outcomes in heart failure patients with preserved ejection fraction Mortality, readmission, and functional decline

AbstractObjectivesWe evaluated the six-month clinical trajectory of patients hospitalized for heart failure (HF) with preserved ejection fraction (EF), as the natural history of this condition has not been well established. We compared mortality, hospital readmission, and changes in functional status in patients with preserved versus depressed EF.BackgroundAlthough the poor prognosis of HF with depressed EF has been extensively documented, there are only limited and conflicting data concerning clinical outcomes for patients with preserved EF.MethodsWe prospectively evaluated 413 patients hospitalized for HF to determine whether EF ≥40% was an independent predictor of mortality, readmission, and the combined outcome of functional decline or death.ResultsAfter six months, 13% of patients with preserved EF died, compared with 21% of patients with depressed EF (p = 0.02). However, the rates of functional decline were similar among those with preserved and depressed EF (30% vs. 23%, respectively; p = 0.14). After adjusting for demographic and clinical covariates, preserved EF was associated with a lower risk of death (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.26 to 0.90; p = 0.02), but there was no difference in the risk of readmission (HR 1.01, 95% CI 0.72 to 1.43; p = 0.96) or the odds of functional decline or death (OR 1.01, 95% CI 0.59 to 1.72; p = 0.97).ConclusionsHeart failure with preserved EF confers a considerable burden on patients, with the risk of readmission, disability, and symptoms subsequent to hospital discharge, comparable to that of HF patients with depressed EF

Intestinal barrier dysfunction in inflammatory bowel diseases

The etiology of human inflammatory bowel diseases (IBDs) is believed to involve inappropriate host responses to the complex commensal microbial flora in the gut, although an altered commensal flora is not completely excluded. A multifunctional cellular and secreted barrier separates the microbial flora from host tissues. Altered function of this barrier remains a major largely unexplored pathway to IBD. Although there is evidence of barrier dysfunction in IBD, it remains unclear whether this is a primary contributor to disease or a consequence of mucosal inflammation. Recent evidence from animal models demonstrating that genetic defects restricted to the epithelium can initiate intestinal inflammation in the presence of normal underlying immunity has refocused attention on epithelial dysfunction in IBD. We review the components of the secreted and cellular barrier, their regulation, including interactions with underlying innate and adaptive immunity, evidence from animal models of the barrier's role in preventing intestinal inflammation, and evidence of barrier dysfunction in both Crohn's disease and ulcerative colitis. (Inflamm Bowel Dis 2008

Unfolding dynamics of proteins under applied force

Understanding the mechanisms of protein folding is a major challenge that is being addressed effectively by collaboration between researchers in the physical and life sciences. Recently, it has become possible to mechanically unfold proteins by pulling on their two termini using local force probes such as the atomic force microscope. Here, we present data from experiments in which synthetic protein polymers designed to mimic naturally occurring polyproteins have been mechanically unfolded. For many years protein folding dynamics have been studied using chemical denaturation, and we therefore firstly discuss our mechanical unfolding data in the context of such experiments and show that the two unfolding mechanisms are not the same, at least for the proteins studied here. We also report unexpected observations that indicate a history effect in the observed unfolding forces of polymeric proteins and explain this in terms of the changing number of domains remaining to unfold and the increasing compliance of the lengthening unstructured polypeptide chain produced each time a domain unfolds

Faecal sludge simulants to aid the development of desludging technologies

This paper presents a review of currently available data from the literature on the undrained shear strength, bulk density, stickiness and debris content of faecal sludge. Those data have been used to develop two different simulants that replicate the full range of shear strengths and densities reported for faecal sludge. Comprehensive specifications are also presented for the debris or solid waste found in latrines to more closely replicate the challenge of pumping faecal sludge. Finally, a design guide has been produced to capture these results and support quantitative performance testing of desludging pumps. The simulants have already been used as part of the Bill & Melinda Gates Foundation's Faecal Sludge Omni-Ingestor project and by Water for People's SaniHub in developing improved desludging pumps. The wider use of these simulants could accelerate the development of pit emptying technologies and help standardize the quantitative evaluation of their performance.The development of the simulants presented here was funded by the Bill & Melinda Gates Foundation under the Faecal Sludge Omni-Ingestor project.This is the author accepted manuscript. The final version is available from IWA Publishing via http://dx.doi.org/10.2166/washdev.2015.01

Crystal structure of monomeric human β-2- microglobulin reveals clues to its amyloidogenic properties

Dissociation of human β-2-microglobulin (β(2)m) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric β(2)m increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human β(2)m determined at 1.8-Å resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a β bulge that separates two short β strands to form a new six-residue β strand at one edge of this β sandwich protein. These structural changes remove key features proposed to have evolved to protect β sheet proteins from aggregation [Richardson, J.&Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754–2759] and replaces them with an aggregationcompetent surface. In combination with solution studies using (1)H NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein

A multi-national European cross-sectional study of feline calicivirus epidemiology, diversity and vaccine cross-reactivity

Background Feline calicivirus (FCV) is an important pathogen of cats for which vaccination is regularly practised. Long-term use of established vaccine antigens raises the theoretical possibility that field viruses could become resistant. This study aimed to assess the current ability of the FCV-F9 vaccine strain to neutralise a randomly collected contemporary panel of FCV field strains collected prospectively in six European countries. Methods Veterinary practices (64) were randomly selected from six countries (UK, Sweden, Netherlands, Germany, France and Italy). Oropharyngeal swabs were requested from 30 (UK) and 40 (other countries) cats attending each practice. Presence of FCV was determined by virus isolation, and risk factors for FCV shedding assessed by multivariable logistic regression. Phylogenetic analyses were used to describe the FCV population structure. In vitro virus neutralisation assays were performed to evaluate FCV-F9 cross-reactivity using plasma from four vaccinated cats. Results The overall prevalence of FCV was 9.2%. Risk factors positively associated with FCV shedding included multi-cat households, chronic gingivostomatitis, younger age, not being neutered, as well as residing in certain countries. Phylogenetic analysis showed extensive variability and no countrywide clusters. Despite being first isolated in the 1950s, FCV-F9 clustered with contemporary field isolates. Plasma raised to FCV-F9 neutralized 97% of tested isolates (titres 1:4 to 1:5792), with 26.5%, 35.7% and 50% of isolates being neutralized by 5, 10 and 20 antibody units respectively. Conclusions This study represents the largest prospective analysis of FCV diversity and antigenic cross-reactivity at a European level. The scale and random nature of sampling used gives confidence that the FCV isolates used are broadly representative of FCVs that cats are exposed to in these countries. The in vitro neutralisation results suggest that antibodies raised to FCV-F9 remain broadly cross-reactive to contemporary FCV isolates across the European countries sampled

Let’s CHAT (community health approaches to) dementia in Aboriginal and Torres Strait Islander communities: protocol for a stepped wedge cluster randomised controlled trial

Background: Documented rates of dementia and cognitive impairment not dementia (CIND) in older Aboriginal and Torres Strait Islander Peoples is 3–5 times higher than the rest of the population, and current evidence suggests this condition is under-diagnosed and under-managed in a clinical primary care setting. This study aims to implement and evaluate a culturally responsive best practice model of care to optimise the detection and management of people with cognitive impairment and/or dementia, and to improve the quality of life of carers and older Aboriginal and Torres Islander Peoples with cognitive impairment. Methods/design: The prospective study will use a stepped-wedge cluster randomised controlled trial design working with 12 Aboriginal Community Controlled Health Services (ACCHSs) across four states of Australia. Utilising a co-design approach, health system adaptations will be implemented including (i) development of a best practice guide for cognitive impairment and dementia in Aboriginal and Torres Strait Islander communities (ii) education programs for health professionals supported by local champions and (iii) development of decision support systems for local medical software. In addition, the study will utilise a knowledge translation framework, the Integrated Promoting Action on Research Implementation in Health Services (iPARIHS) Framework, to promote long-term sustainable practice change. Process evaluation will also be undertaken to measure the quality, fidelity and contextual influences on the outcomes of the implementation. The primary outcome measures will be rates of documentation of dementia and CIND, and evidence of improved management of dementia and CIND among older Indigenous peoples attending Aboriginal and Torres Strait Islander primary care services through health system changes. The secondary outcomes will be improvements to the quality of life of older Indigenous peoples with dementia and CIND, as well as that of their carers and families. Discussion: The Let’s CHAT Dementia project will co-design, implement and evaluate a culturally responsive best practice model of care embedded within current Indigenous primary health care. The best practice model of care has the potential to optimise the timely detection (especially in the early stages) and improve the ongoing management of people with dementia or cognitive impairment