Interactions between soil, toxicant, and a lux-marked bacterium during solid phase-contact toxicity testing

Bioluminescence-based, solid-contact toxicity assays allow test bacterium and toxicant to interact at the solid-solution interface. A lux- marked bacterium, Burkholderia sp. RASC, and 2,4-dichlorophenol (2,4-DCP) were used to characterize these interactions. In the basic bioassay, cells were added to soil slurries containing 2,4-DCP (0-120 μg ml^-1). After 15 min, soil was removed by centrifugation, and bioluminescence in the supernatant was determined. Investigation of 2,4-DCP adsorption to soil revealed that sorption was linear and not significantly (p > 0.1) affected by the presence of Burkholderia cells. The numbers of culturable Burkholderia cells in the assay supernatant were 48.2 to 64.8% of the inoculum and independent of the soil weight. The effect of soil on 2,4-DCP toxicity was investigated by comparing soil aqueous extract and contact assays. The percentage bioluminescence for the contact assay was consistently higher than the extract assay at all test concentrations, and counts of viable Burkholderia cells were enhanced by the presence of 2,4-DCP in the contact assay. Expressing results as specific bioluminescence decreased the variability in response and the discrepancy in results between the two protocols. We suggest that solid-contact assays need improvement to ensure defined contact between cells and solid phase, and that the reporting of specific activity should be emphasized.

Micromechanical analysis of cohesive granular materials using the discrete element method with an adhesive elasto-plastic contact model

An adhesive elasto-plastic contact model for the discrete element method with three dimensional non-spherical particles is proposed and investigated to achieve quantitative prediction of cohesive powder flowability. Simulations have been performed for uniaxial consolidation followed by unconfined compression to failure using this model. The model has been shown to be capable of predicting the experimental flow function (unconfined compressive strength vs. the prior consolidation stress) for a limestone powder which has been selected as a reference solid in the Europe wide PARDEM research network. Contact plasticity in the model is shown to affect the flowability significantly and is thus essential for producing satisfactory computations of the behaviour of a cohesive granular material. The model predicts a linear relationship between a normalized unconfined compressive strength and the product of coordination number and solid fraction. This linear relationship is in line with the Rumpf model for the tensile strength of particulate agglomerate. Even when the contact adhesion is forced to remain constant, the increasing unconfined strength arising from stress consolidation is still predicted, which has its origin in the contact plasticity leading to microstructural evolution of the coordination number. The filled porosity is predicted to increase as the contact adhesion increases. Under confined compression, the porosity reduces more gradually for the load-dependent adhesion compared to constant adhesion. It was found that the contribution of adhesive force to the limiting friction has a significant effect on the bulk unconfined strength. The results provide new insights and propose a micromechanical based measure for characterising the strength and flowability of cohesive granular materials. 

Recognition of O6MeG lesions by MGMT and mismatch repair proficiency may be a prerequisite for low-dose radiation hypersensitivity

Low-dose hyper-radiosensitivity (HRS) is the phenomenon whereby cells exposed to radiation doses of less than approximately 0.5 Gy exhibit increased cell killing relative to that predicted from back-extrapolating high-dose survival data using a linear-quadratic model. While the exact mechanism remains to be elucidated, the involvement of several molecular repair pathways has been documented. These processes in turn are also associated with the response of cells to O6-methylguanine (O6MeG) lesions. We propose a model in which the level of low-dose cell killing is determined by the efficiency of both pre-replicative repair by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) and post-replicative repair by the DNA mismatch repair (MMR) system. We therefore hypothesized that the response of cells to low doses of radiation is dependent on the expression status of MGMT and MMR proteins. MMR (MSH2, MSH6, MLH1, PMS1, PMS2) and MGMT protein expression signatures were determined in a panel of normal (PWR1E, RWPE1) and malignant (22RV1, DU145, PC3) prostate cell lines and correlated with clonogenic survival and cell cycle analysis. PC3 and RWPE1 cells (HRS positive) were associated with MGMT and MMR proficiency, whereas HRS negative cell lines lacked expression of at least one (MGMT or MMR) protein. MGMT inactivation had no significant effect on cell survival. These results indicate a possible role for MMR-dependent processing of damage produced by low doses of radiation.

Eight International London Cough Symposium 2014: Cough hypersensitivity syndrome as the basis for chronic cough

At the Eighth International London Cough Conference held in London in July 2014, the focus was on the relatively novel concept of cough hypersensitivity syndrome (CHS) as forming the basis of chronic cough. This concept has been formulated following understanding of the neuronal pathways for cough and a realisation that not all chronic cough is usually associated with a cause. The CHS is defined by troublesome coughing triggered by low level of thermal, mechanical or chemical exposure. It also encompasses other symptoms or sensations such as laryngeal hypersensitivity, nasal hypersensitivity and possibly also symptoms related to gastrooesopahgeal reflux. The pathophysiologic basis of the CHS is now being increasingly linked to an enhancement of the afferent pathways of the cough reflex both at the peripheral and central levels. Mechanisms involved include the interactions of inflammatory mechanisms with cough sensors in the upper airways and with neuronal pathways of cough, associated with a central component. Tools for assessing CHS in the clinic need to be developed. New drugs may be developed to control CHS. A roadmap is suggested from the inception of the CHS concept towards the development of newer antitussives at the Symposium.

PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.

Confidence in Contact: A New Perspective on Promoting Cross-Group Friendship Among Children and Adolescents

Intergroup contact theory proposes that positive interactions between members of different social groups can improve intergroup relations. Contact should be especially effective in schools, where opportunities may exist to engage cooperatively with peers from different backgrounds and develop cross-group friendships. In turn, these friendships have numerous benefits for intergroup relations. However, there is evidence that children do not always engage in cross-group friendships, often choosing to spend time with same-group peers, even in diverse settings. We argue that in order to capitalize on the potential impact of contact in schools for promoting harmonious intergroup relations, a new model is needed that places confidence in contact at its heart. We present an empirically driven theoretical model of intergroup contact that outlines the conditions that help to make young people contact ready, preparing them for successful, sustained intergroup relationships by giving them the confidence that they can engage in contact successfully. After evaluating the traditional approach to intergroup contact in schools, we present our theoretical model which outlines predictors of cross-group friendships that enhance confidence in and readiness for contact. We then discuss theory-driven, empirically tested interventions that could potentially promote confidence in contact. Finally, we make specific recommendations for practitioners and policy makers striving to promote harmonious intergroup relations in the classroom.

Paramountcy, family rights and contested adoption: does contact with birth relatives balance the scales?

This article combines practitioner insight and research evidence to chart how principles of partnership and paramountcy have led to birth family contact becoming the expected norm following contested adoption from care in Northern Ireland. The article highlights how practice has adapted to the delay in proposed reforms to adoption legislation resulting in the evolution of increasingly open adoption practices. Adoption represents an irrevocable transfer of parental responsibility from birth to adoptive parents and achieves permanence and legal security for children in care who cannot return to their birth family. Its enduring effect, however, makes public adoption a contentious field of child welfare practice, particularly when contested by birth parents. This article explores how post-adoption contact may be viewed as reconciling the uneasy interface between paramountcy principles and parental rights to respect for family life. The article highlights the complexity of adoptive kinship relationships following contested adoption from care, and how contact presents unique challenges that mitigate against meaningful and sustainable connections between the child and their birth relatives. In conclusion, a call is made for sensitive negotiation and support of contact arrangements, and the development of practice models that are informed by an understanding of the workings of adoptive kinship.