Silencing of TESTIN by dense biallelic promoter methylation is the most common molecular event in childhood acute lymphoblastic leukaemia

<p>Abstract</p> <p>Background</p> <p>Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome. However, few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. By screening candidate genes, we have detected frequent and dense methylation of the <it>TESTIN </it>(<it>TES</it>) promoter.</p> <p>Results</p> <p>Bisulfite sequencing showed that 100% of the ALL samples (n = 20) were methylated at the <it>TES </it>promoter, whereas the matched remission (n = 5), normal bone marrow (n = 6) and normal PBL (n = 5) samples were unmethylated. Expression of <it>TES </it>in hyperdiploid, TEL-AML⁺, BCR-ABL⁺, and E2A-PBX⁺subtypes of B lineage ALL was markedly reduced compared to that in normal bone marrow progenitor cells and in B cells. In addition <it>TES </it>methylation and silencing was demonstrated in nine out of ten independent B ALL propagated as xenografts in NOD/SCID mice.</p> <p>Conclusion</p> <p>In total, 93% of B ALL samples (93 of 100) demonstrated methylation with silencing or reduced expression of the <it>TES </it>gene. Thus, <it>TES </it>is the most frequently methylated and silenced gene yet reported in ALL. <it>TES</it>, a LIM domain-containing tumour suppressor gene and component of the focal adhesion complex, is involved in adhesion, motility, cell-to-cell interactions and cell signalling. Our data implicate <it>TES </it>methylation in ALL and provide additional evidence for the involvement of LIM domain proteins in leukaemogenesis.</p

Support My Spine ASAP. A Rural Tele-health care model for patients being managed with a Thoracic Lumbar Sacral Orthotic (TLSO).

U ovom diplomskom radu definirana je i ispitana nova metoda kratkoročne prognoze valnih visina iz podataka brzine vjetra tzv. metoda ekvivalentnog trajanja. Metoda je bazirana na jednadžbama danim u EM 1110-2-1100 (Part II) Chapter II-2 “Meteorology and Wave Climate”. Projektiranje pomorskih građevina gotovo uvijek zahtijeva prognozu određenih parametara valova. To je prognoziranje često vrlo komplicirano te zahtijeva suradnju projektanta i inženjera specijaliziranog za izradu kompleksnih numeričkih modela. U nekim situacijama poželjno je procijeniti značajne valne visine koje se mogu pojaviti na nekom prostoru na jednostavan, jeftin i brz način. U svrhu istraživanja u ovome radu analizirane su valne situacije na dvije lokacije, u Riječkom zaljevu te kod mjesta Rukavac na otoku Visu. Uspoređujući izmjerene valne visine u trenutku pojave maksimalne brzine i valne visine dobivene proračunom, utvrđeno je da metoda ekvivalentnog trajanja bazirana na jednadžbama danim u EM 1110-2-1100 (Part II) Chapter II-2 “Meteorology and Wave Climate” značajno podcjenjuje vrijednosti značajnih valnih visina. U ovom radu ispitano je 17 valnih situacija te su na njima testirane dvije modifikacije bazne metode ekvivalentnog trajanja. Rezultati dviju modifikacije su vrijednosti značajnih valnih visina i perioda značajno bliže izmjerenim vrijednostima, odnosno vrijednostima dobivenim iz globalnog modela.A research study has been conducted to estimate significant wave heights and wave periods for wind-generated waves using the new equivalent duration method based on the equations from EM 1110-2-1100 (Part II) Chapter II-2 “Meteorology and Wave Climate”. Designing maritime structures almost always requires wave hindcasting and forecasting. In some cases it is desirable to estimate significant wave heights and periods in a simple, inexpensive and quick way without complex, numerical models or expensive software. For the purpose of this research study, wind-wave situations on two locations have been analysed. The first one in the Rijeka bay area and the second one close to Rukavac on the island of Vis. Comparing the measured and calculated significant wave heights in the moment of maximum wind speed, it has been noticed that the equivalent duration method based on the equations from EM 1110-21100 (Part II) Chapter II-2 “Meteorology and Wave Climate” underestimates the values of calculated wave heights. In this research study two new modifications of the basic method, on 17 wind-wave situations, have been tested. The results show that the values of calculated significant wave heights and wave periods in the moment of maximum wind speed are closer to the measured values

Support My Spine ASAP. A Rural Tele-health care model for patients being managed with a Thoracic Lumbar Sacral Orthotic (TLSO).

Question: Does a Telehealth model of care facilitating treatment in rural hospitals for patients requiring a TLSO eliminate the need for transfer to a tertiary referral hospital? Design: Quantitative pre and post intervention design. Participants: Physiotherapists, nursing and medical staff at rural hospital pilot sites. Intervention: Pre and post intervention data collection provided patient demographics, and length of stay data around model of care implementation. Pre intervention staff surveys identified knowledge gaps informing educational packages which were provided with a mobile Telehealth link. Outcome measures: Primary: Number of patients managed under the new model of care. Secondary: Length of stay, travel distance eliminated and complications. Results: 30 patients fitted with TLSO’s and managed under this model of care to date. Length of stay has reduced from 9.14 days pre intervention to 3.8 days post intervention. Approximate savings of $6840 per patient have been identified, with over 6000kms of patient travel eliminated. No complications have occurred. Rural Physiotherapists have been successfully up skilled in managing patients requiring TLSO fitting. Conclusion: This intervention successfully created a model of care to facilitate local management of patients requiring TLSO fitting with Telehealth support from a tertiary referral hospital. Considerable savings have occurred from this model of care for patients and the health district. This model is currently being implemented district wide. Key Practice Points: Telehealth model of care can be successfully implemented to TLSO management Multidisciplinary team role is critical role in redesigning models of care Telehealth increase the efficiency of healthcare resource

PrEP as a feature in the optimal landscape of combination HIV prevention in sub-Saharan Africa

INTRODUCTION: The new WHO guidelines recommend offering pre-exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub-Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape. METHODS: We use a model that was previously developed to capture subnational HIV transmission in sub-Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub-Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold. RESULTS: At low-to-moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions. CONCLUSIONS: Our findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost-effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost-effective HIV response across Africa

Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10−4, permutation p = 1.0×10−3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10−7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases

A cross-sector analysis of human and organisational factors in the deployment of data-driven predictive maintenance

Domains such as utilities, power generation, manufacturing and transport are increasingly turning to data-driven tools for management and maintenance of key assets. Whole ecosystems of sensors and analytical tools can provide complex, predictive views of network asset performance. Much research in this area has looked at the technology to provide both sensing and analysis tools. The reality in the field, however, is that the deployment of these technologies can be problematic due to user issues, such as interpretation of data or embedding within processes, and organisational issues, such as business change to gain value from asset analysis. 13 experts from the field of remote condition monitoring, asset management and predictive analytics across multiple sectors were interviewed to ascertain their experience of supplying data-driven applications. The results of these interviews are summarised as a framework based on a predictive maintenance project lifecycle covering project motivations and conception, design and development, and operation. These results identified critical themes for success around having a target or decision-led, rather than data-led, approach to design; long-term resourcing of the deployment; the complexity of supply chains to provide data-driven solutions and the need to maintain knowledge across the supply chain; the importance of fostering technical competency in end-user organisations; and the importance of a maintenance-driven strategy in the deployment of data-driven asset management. Emerging from these themes are recommendations related to culture, delivery process, resourcing, supply chain collaboration and industry-wide cooperation

Marine Litter : Technical Recommendations for the Implementation of MSFD Requirements

As a follow up to the Commission Decision on criteria and methodological standards on good environmental status (GES) of marine waters (Commission Decision 2010/477/EU), the Marine Directors requested Directorate General Environment in 2010 to establish a technical subgroup under the Working Group on GES in relation to the Marine Strategy Framework Directive 2008/56/EC (WG GES) for further development of Descriptor 10 Marine Litter and Descriptor 11 Noise/Energy. This report compiles the recommendations regarding Descriptor 10, Marine Litter. The implementation of provisons under MSFD Descriptor 10 as described in the Commission Decision 2010/477/EU is in its first step depending on the availability of appropriate monitoring tools.The group has investigated the monitoring approaches for marine litter and provides a set of monitoring tools which can be employed for that purpose.There are gaps in the regional applicability and differences in the maturity of some tools. There is need for further harmonization and collaborative activities in order to allow EU MS the future reporting of environmental trends and thus the verification of measures against marine litter.JRC.H.5-Rural, water and ecosystem resource

Investigating the role of prior and observation error correlations in improving a model forecast of forest carbon balance using Four Dimensional Variational data assimilation

Efforts to implement variational data assimilation routines with functional ecology models and land surface models have been limited, with sequential and Markov chain Monte Carlo data assimilation methods being prevalent. When data assimilation has been used with models of carbon balance, prior or “background” errors (in the initial state and parameter values) and observation errors have largely been treated as independent and uncorrelated. Correlations between background errors have long been known to be a key aspect of data assimilation in numerical weather prediction. More recently, it has been shown that accounting for correlated observation errors in the assimilation algorithm can considerably improve data assimilation results and forecasts. In this paper we implement a Four-Dimensional Variational data assimilation (4D-Var) scheme with a simple model of forest carbon balance, for joint parameter and state estimation and assimilate daily observations of Net Ecosystem CO2 Exchange (NEE) taken at the Alice Holt forest CO2 flux site in Hampshire, UK. We then investigate the effect of specifying correlations between parameter and state variables in background error statistics and the effect of specifying correlations in time between observation errors. The idea of including these correlations in time is new and has not been previously explored in carbon balance model data assimilation. In data assimilation, background and observation error statistics are often described by the background error covariance matrix and the observation error covariance matrix. We outline novel methods for creating correlated versions of these matrices, using a set of previously postulated dynamical constraints to include correlations in the background error statistics and a Gaussian correlation function to include time correlations in the observation error statistics. The methods used in this paper will allow the inclusion of time correlations between many different observation types in the assimilation algorithm, meaning that previously neglected information can be accounted for. In our experiments we assimilate a single year of NEE observations and then run a forecast for the next 14 years. We compare the results using our new correlated background and observation error covariance matrices and those using diagonal covariance matrices. We find that using the new correlated matrices reduces the root mean square error in the 14 year forecast of daily NEE by 44% decreasing from 4.22 gCm−2 day−1 to 2.38 gCm−2 day−