Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest

TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.Publisher PDFPeer reviewe

Uplift Capacity of Driven Piles from Static Loading Tests

A pile driving and testing program was undertaken to evaluate installation procedures, assess capacity (particularly in uplift) of 24- and 30-inch square, prestressed concrete piles, and provide foundation design parameters for the New Edison Bridge project in Fort Myers, Florida. The subsurface profile generally consisted of three major soil strata: an upper clayey sand and sandy clay layer to a depth of about 45 to 50 feet below mudline, a medium dense to dense silty sand middle layer about 10 feet thick, and a third layer of dense to very dense silty fine sand. Eleven prestressed concrete test piles of varying length were driven at five test sites and uplift tests were performed to allow an independent evaluation of the different soil layers. All piles were dynamically monitored during installation and restrikes to evaluate pile drivability and bearing capacity including time related capacity increases due to soil set-up. This paper presents descriptions of the pile driving and load testing program along with findings regarding pile uplift capacities from load tests, pile capacities from dynamic testing, soil-pile adhesion values, wave equation factors, soil strength vs time dependency, foundation design and pile driving recommendations

The 2HA line of Medicago truncatula has characteristics of an epigenetic mutant that is weakly ethylene insensitive

BACKGROUND The Medicago truncatula 2HA seed line is highly embryogenic while the parental line Jemalong rarely produces embryos. The 2HA line was developed from one of the rare Jemalong regenerates and this method for obtaining a highly regenerable genotype in M. truncatula is readily reproducible suggesting an epigenetic mechanism. Microarray transcriptomic analysis showed down regulation of an ETHYLENE INSENSITIVE 3-like gene in 2HA callus which provided an approach to investigating epigenetic regulation of genes related to ethylene signalling and the 2HA phenotype. Ethylene is involved in many developmental processes including somatic embryogenesis (SE) and is associated with stress responses. RESULTS Microarray transcriptomic analysis showed a significant number of up-regulated transcripts in 2HA tissue culture, including nodule and embryo specific genes and transposon-like genes, while only a few genes were down-regulated, including an EIN3-like gene we called MtEIL1. This reduced expression was associated with ethylene insensitivity of 2HA plants that was further investigated. The weak ethylene insensitivity affected root and nodule development. Sequencing of MtEIL1 found no difference between 2HA and wild-type plants. DNA methylation analysis of MtEIL1 revealed significant difference between 2HA and wild-type plants. Tiling arrays demonstrated an elevated level of miRNA in 2HA plants that hybridised to the antisense strand of the MtEIL1 gene. AFLP-like methylation profiling revealed more differences in DNA methylation between 2HA and wild-type. Segregation analysis demonstrated the recessive nature of the eil1 phenotype and the dominant nature of the SE trait. CONCLUSIONS We have demonstrated that EIL1 of Medicago truncatula (MtEIL1) is epigenetically silenced in the 2HA seed line. The possible cause is an elevated level of miRNA that targets its 3'UTR and is also associated with DNA methylation of MtEIL1. Down regulation of MtEIL1 makes it possible to form nodules in the presence of ethylene and affects root growth under normal conditions. Segregation analysis showed no association between MtEIL1 expression and SE in culture but the role and mechanism of ethylene signalling in the process of plant regeneration through SE requires further investigation. The work also suggests that epigenetic changes to a particular gene induced in culture can be fixed in regenerated plants.This work was funded by the Australian Research Council (CEO348212) through the ARC Centre of Excellence for Integrative Legume Research (CILR)

Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer : diagnostic and therapeutic potential

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC

Cyclic Multi-Directional Response of Clay Deposits: Evaluating a Constitutive Model

The focus of this study is to verify the capabilities of a constitutive model to mimic a wide range of monotonic and cyclic multi-directional stress paths in clays. The generalized elasto-plastic constitutive formulation of the model enables to describe stress-strain response, accumulation of permanent deformations and excess pore pressure in monotonic and multi-directional cyclic loading. The model is calibrated based on the experimental database on the Gulf of Mexico clay developed at Texas A&M, including the constant rate strain (CRS) consolidation as well as monotonic triaxial tests. Capabilities of the calibrated model to predict the cyclic multi-directional stress paths are then evaluated through comparison with the results of cyclic, circular, and figure 8 multi-directional simple shear tests as a part of the Gulf of Mexico clay experimental database. We also used the extensive database for Boston Blue Clay (BBC) to calibrate model constants and verify its capabilities to mimic the monotonic and cyclic response of lower plasticity clays. The model proves successful to predict a wide range of complicated cyclic multi-directional stress paths for clays

Facility-level characteristics associated with family planning and child immunization services integration in urban areas of Nigeria: a longitudinal analysis

Background: Unmet need for postpartum contraception is high. Integration of family planning with routine child immunization services may help to satisfy unmet need. However, evidence about the determinants and effects of integration has been inconsistent, and more evidence is required to ascertain whether and how to invest in integration. In this study, facility-level family planning and immunization integration index scores are used to: (1) determine whether integration changes over time and (2) identify whether facility-level characteristics, including exposure to the Nigerian Urban Reproductive Health Initiative (NURHI), are associated with integration across facilities in six urban areas of Nigeria. Methods: This study utilizes health facility data collected at baseline (n = 400) and endline (n = 385) for the NURHI impact evaluation. Difference-in-differences models estimate the associations between facility-level characteristics, including exposure to NURHI, and Provider and Facility Integration Index scores. The two outcome measures, Provider and Facility Integration Index scores, reflect attributes that support integrated service delivery. These indexes, which range from 0 (low) to 10 (high), were constructed using principal component analysis. Scores were calculated for each facility. Independent variables are (1) time period, (2) whether the facility received the NURHI intervention, and (3) additional facility-level characteristics. Results: Within intervention facilities, mean Provider Integration Index scores were 6.46 at baseline and 6.79 at endline; mean Facility Integration Index scores were 7.16 (baseline) and 7.36 (endline). Within non-intervention facilities, mean Provider Integration Index scores were 5.01 at baseline and 6.25 at endline; mean Facility Integration Index scores were 5.83 (baseline) and 6.12 (endline). Provider Integration Index scores increased significantly (p = 0.00) among non-intervention facilities. Facility Integration Index scores did not increase significantly in either group. Results identify facility-level characteristics associated with higher levels of integration, including smaller family planning client load, family planning training among providers, and public facility ownership. Exposure to NURHI was not associated with integration index scores. Conclusion: Programs aiming to increase integration of family planning and immunization services should monitor and provide targeted support for the implementation of a well-defined integration strategy that considers the influence of facility characteristics and concurrent initiatives

Development of integration indexes to determine the extent of family planning and child immunization services integration in health facilities in urban areas of Nigeria

Background: Integrating family planning into child immunization services may address unmet need for contraception by offering family planning information and services to postpartum women during routine child immunization visits. However, policies and programs promoting integration are often based on insubstantial or conflicting evidence about its effects on service delivery and health outcomes. While integration models vary, many studies measure integration as binary (a facility is integrated or not) rather than a multidimensional and varying continuum. It is thus challenging to ascertain the determinants and effects of integrated service delivery. This study creates Facility and Provider Integration Indexes, which measure capacity to support integrated family planning and child immunization services and applies them to analyze the extent of integration across 400 health facilities. Methods: This study utilizes cross-sectional health facility (N = 400; 58% hospitals, 42% primary healthcare centers) and healthcare provider (N = 1479) survey data that were collected in six urban areas of Nigeria for the impact evaluation of the Nigerian Urban Reproductive Health Initiative. Principal Component Analysis was used to develop Provider and Facility Integration Indexes that estimate the extent of integration in these health facilities. The Provider Integration Index measures provider skills and practices that support integrated service delivery while the Facility Integration Index measures facility norms that support integrated service delivery. Index scores range from zero (low) to ten (high). Results: Mean Provider Integration Index score is 5.42 (SD 3.10), and mean Facility Integration Index score is 6.22 (SD 2.72). Twenty-three percent of facilities were classified as having low Provider Integration scores, 32% as medium, and 45% as high. Fourteen percent of facilities were classified as having low Facility Integration scores, 38% as medium, and 48% as high. Conclusion: Many facilities in our sample have achieved high levels of integration, while many others have not. Results suggest that using more nuanced measures of integration may (a) more accurately reflect true variation in integration within and across health facilities, (b) enable more precise measurement of the determinants or effects of integration, and (c) provide more tailored, actionable information about how best to improve integration. Overall, results reinforce the importance of utilizing more nuanced measures of facility-level integration