The role of IKK-induced NF-kB1 p105 proteolysis in T lymphocytes

Proteolysis of NF-kB1 p105 is vital for its function as a precursor to p50 and as an IkB. This occurs in two ways, both mediated by the proteasome. A constitutive proteolytic removal of the p105 C-terminus, termed processing, generates the mature transcription factor p50. In contrast, a signal-induced p105 proteolysis is triggered by phosphorylation of serines 927 and 932 in the p105 PEST region by the IKK complex. This promotes p105 poly-ubiquitination and subsequent complete degradation. IKK-induced p105 proteolysis has been demonstrated to regulate the kinase activity of the MAP3K TPL-2, since all detectable TPL-2 is found in a complex with p105. Furthermore, NF-kB1 p105 retains Rel subunits in the cytoplasm via interaction with the p105 C-terminal ankyrin repeat region. However, it is unclear whether IKK-induced p105 proteolysis contributes to NF-kB activation, though this process would be expected to release Rel subunits to translocate into the nucleus. A large body of evidence exists to suggest a major role for NF-kB in T cell development and function. To investigate the significance of IKK-induced p105 degradation in T cells, a knock-in mouse strain, Nfkb1S927A'S93ZA, in which serines 927 and 932 of NF-kB1 p105 were mutated to alanine residues was analysed. Previous work has shown that constitutive processing of pio5S927A S932A to p50 occurs normally, but this mutated p105 is refractory to IKK-induced proteolysis. Work presented here demonstrates that whilst p105 mutation did not affect thymic differentiation of CD4+ and CD8+ T cells, numbers of CD4+CD25+ regulatory T cells, memory-phenotype CD4+ T cells and thymic NKT cells were significantly reduced. Analysis of BM chimeras revealed cell autonomous and non-haematopoietic defects required for generation of these sub-populations. In vitro experiments indicated that TCR-induced proliferation was significantly impaired in /Vflcb7S927A S932A CD4+ T cells, due partly to reduced interleukin-2 production. In contrast, p105 mutation had no effect on CD4+ T cell survival. These defects were not due to a lack of TPL-2 activity, based on analysis of TPL-2-deficient mice. This study presents evidence to suggest a critical role for IKK-induced p105 proteolysis in regulating NF-kB activation in T lymphocytes

Experimental evaluation of kaolin stabilised with class F fly ash

This study aims to investigate the effectiveness of fly ash (FA) in stabilising a kaolin soil through laboratory tests. Kaolin is an example of moderate plasticity clays that require stabilisation methods for construction purposes. The influence of FA on the improvement of kaolin is studied by varying its dosages in the mixtures (0%, 10% to 20%) as well as the cement content, used as an activator in different percentages (5 and 7%). The influence of the dry unit weight and the curing time of the soil mixture is also analysed through unconfined compressive strength and indirect tensile strength tests. The experimental results show that the strength increases linearly with both FA and cement contents. Moreover, higher initial dry unit weights also yield higher final strengths. To further assess the improvement, the application of the porosity over the volumetric cement content ratio, as the main variable, succeeded in attaining a relationship with the strength and the stiffness of the studied soil. Results for the combined effect of the porosity and the volumetric cement on the secant modulus were also determined. Furthermore, a unique relationship was obtained combining porosity, volumetric cement and FA content

Pilot Study: The analysis of known physical mixtures mimicking heroin samples using X Ray Powder Diffraction for the purposeof qualitative and quantitative analysis

The illegal use of drugs is a major issue, and it is estimated that globally 210 million people aged 15-64 had used an illicit substance at least once. Heroin is one of the most problematic drugs and there is a high fatality rate as a result. The increasing trend in global seizures suggests that there is an increase in production of heroin. Current drug analysis involves qualitative and quantitative determinations using techniques such as Gas Chromatography (GC) and/ or Liquid Chromatography- Mass Spectrometry (LC-MS). Profiling of suspected drugs requires a further evaluation of the chromatographic and spectroscopic data along with further testing. The use of XRPD for the purpose of drug analysis is rare in the field of Forensic Science. It is a non-destructive technique preserving the sample analysed for further investigation if required. This study aims to demonstrate the capability of X-Ray Powder Diffractometry as a tool for simultaneous qualitative and quantitative analysis of known physical mixtures mimicking heroin samples. A suitable method was developed to analyse known mixtures containing caffeine, codeine and paracetamol using the Bruker D8 Advance X-ray diffractometer. Following this the method was optimised to improve the qualitative and quantitative capabilities. The data highlighted that a 20 minute runtime using a 0.020° increment size provided accurate and repeatable data using a 50:50 caffeine:paracetamol mixture. Rietveld refinement was used to enable quantitation and provided highly accurate and repeatable results through single (active) component quantitation in the presence of an internal standard over a range of 12.6% w/w to 50.1% w/w

PI3K inhibitors in inflammation, autoimmunity and cancer.

The healthy immune system protects against infection and malignant transformation without causing significant damage to host tissues. Immune dysregulation results in diverse pathologies including autoimmune disease, chronic inflammatory disorders, allergies as well as immune deficiencies and cancer. Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research. In recent years we have gained detailed understanding of PI3K signalling, and saw the development of potent and highly selective small molecule inhibitors, of which several are currently in clinical trials for the treatment of immune-related disorders and cancer. The role of PI3K signalling in the immune response has been the subject of detailed reviews; here we focus on relevant recent progress in pre-clinical and clinical development of PI3K inhibitors

Obituary: Kuan-Teh Jeang.

Dear colleagues: Our loyal friend Kuan-Teh Jeang, "Teh" to friends and colleagues, passed away unexpectedly at the age of 54 on the evening of January 27, 2013. Great shock and sorrow was apparent in the avalanche of email messages by the very many international colleagues with whom Teh interacted over the years. Many of us came to know Teh as an energetic and gifted scientist for whom we had much respect and affection.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Perspectives on enhancing physical activity and diet for health promotion among at-risk urban UK South Asian communities: a qualitative study

Objectives To explore perspectives on enhancing physical activity and diet among South Asians in urban deprived communities at high risk of chronic disease and to inform development of culturally appropriate health promotion intervention. Design Qualitative study using semistructured one-to-one and family group interviews with thematic analysis of data. Setting Urban disadvantaged communities in the East Midlands of the UK. Participants 45 respondents, including 34 people of South Asian origin (16 at-risk individuals, six family groups involving 18 relatives), of mainly Pakistani and Indian origin, including 16 non-English speakers; and 11 health professionals working locally with communities of concern. Results South Asian participants underlined the challenges of requiring family members across generations to engage in modifying dietary behaviours, and the central role of communal eating of traditional ‘Asian’ food in their cultural lives. Barriers to increasing physical activity included cost, personal safety and lack of time outside of long working hours and carer commitments. However, increasing walking activity was regarded as feasible by both community and health professional participants. Respondents emphasised using a social approach for potential interventions, undertaking activity with family or friends and with bilingual community peers to facilitate engagement, motivation and support. Spoken content and delivery of interventions was favoured, including personal stories and multilingual audio–visual information; within local informal rather than provider settings, including the home; and aided by pedometers for self-monitoring. Conclusions Focusing on physical activity by increasing walking may hold promise as health promotion in this deprived South Asian community context. Further intervention development, with exploration of feasibility and acceptability of the social approach and elements suggested, is merited

Barriers and facilitators of physical activity among adults and older adults from Black and Minority Ethnic groups in the UK: A systematic review of qualitative studies

Older adults from Black and Minority Ethnic (BME) groups experience a relatively higher burden of physical inactivity compared with their counterparts from non-BME groups. Despite the increasing number of qualitative studies investigating the barriers and facilitators of physical activity among older adults from BME backgrounds in the UK, there is very limited review-level evidence. The aim of this review is to undertake a synthesis of existing qualitative studies, using a meta-ethnographic approach, to explore the barriers and opportunities for physical activity among adults and older adults from BME communities in the UK.Studies conducted between January 2007 and July 2017 were eligible if they met the following criteria: employed any qualitative method; included participants identified as being BME, aged 50 and above, and living in the UK. In total, 1036 studies were identified from a structured search of six electronic databases combined with hand searching of reference bibliographies. Ten studies met the inclusion criteria for the review and were included.Six key themes emerged from the data: awareness of the links between physical activity and health, interaction and engagement with health professionals, cultural expectations and social responsibilities, suitable environment for physical activity, religious fatalism and practical challenges. There was a substantial gap in research among Black African groups.Interventions aimed at improving physical activity participation among older adults should be acceptable and accessible to minority groups. Further research is needed to investigate the barriers and facilitators of physical activity among older adults from African backgrounds

IKK-induced NF-kappa B1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen

The importance of IκB kinase (IKK)–induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1SSAA/SSAA mice, in which this NF-κB signaling pathway is blocked. Nfkb1SSAA mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1SSAA/SSAA FM B cells were completely unable to mediate T cell–dependent antibody responses. Nfkb1SSAA mutation decreased B cell antigen receptor (BCR) activation of NF-κB in FM B cells, which selectively blocked BCR stimulation of cell survival and antigen-induced differentiation into plasmablasts and germinal center B cells due to reduced expression of Bcl-2 family proteins and IRF4, respectively. In contrast, the antigen-presenting function of FM B cells and their BCR-induced migration to the follicle T cell zone border, as well as their growth and proliferation after BCR stimulation, were not affected. All of the inhibitory effects of Nfkb1SSAA mutation on B cell functions were rescued by normalizing NF-κB activation genetically. Our study identifies critical B cell-intrinsic functions for IKK-induced NF-κB1 p105 proteolysis in the antigen-induced survival and differentiation of FM B cells, which are essential for T-dependent antibody responses

Tissue Specific Deletion of Inhibitor of Kappa B Kinase 2 with OX40-Cre Reveals the Unanticipated Expression from the OX40 Locus in Skin Epidermis

NF-κB signalling plays an essential role in T cell activation and generation of regulatory and memory populations in vivo. In the present study, we aimed to investigate the role of NF-κB signalling in post-activation T cells using tissue specific ablation of inhibitor of kappa-B kinase 2 expression, an important component of the inhibitor of kappa-B kinase complex in canonical NF-κB signalling. The OX40 antigen is expressed on activated T cells. Therefore, we used previously described mouse strain expressing Cre recombinase from the endogenous OX40 locus. Ablation of IKK2 expression using OX40Cre mice resulted in the development of an inflammatory response in the skin epidermis causing wide spread skin lesions. The inflammatory response was characterised by extensive leukocytic infiltrate in skin tissue, hyperplasia of draining lymph nodes and widespread activation in the T cell compartment. Surprisingly, disease development did not depend on T cells but was rather associated with an unanticipated expression of Cre in skin epidermis, and activation of the T cell compartment did not require Ikbk2 deletion in T cells. Employment of Cre reporter strains revealed extensive Cre activity in skin epidermis. Therefore, development of skin lesions was rather more likely explained by deletion of Ikbk2 in skin keratinocytes in OX40Cre mice

Rising atmospheric methane: 2007-2014 growth and isotopic shift

From 2007 to 2013, the globally averaged mole fraction of methane in the atmosphere increased by 5.7±1.2ppb yr$^{-1}$. Simultaneously, $\delta^{13}$C$_\text{CH4}$ (a measure of the $^{13}$C/$^{12}$C isotope ratio in methane) has shifted to significantly more negative values since 2007. Growth was extreme in 2014, at 12.5±0.4ppb, with a further shift to more negative values being observed at most latitudes. The isotopic evidence presented here suggests that the methane rise was dominated by significant increases in biogenic methane emissions, particularly in the tropics, for example, from expansion of tropical wetlands in years with strongly positive rainfall anomalies or emissions from increased agricultural sources such as ruminants and rice paddies. Changes in the removal rate of methane by the OH radical have not been seen in other tracers of atmospheric chemistry and do not appear to explain short-term variations in methane. Fossil fuel emissions may also have grown, but the sustained shift to more $^{13}$C-depleted values and its significant interannual variability, and the tropical and Southern Hemisphere loci of post-2007 growth, both indicate that fossil fuel emissions have not been the dominant factor driving the increase. A major cause of increased tropical wetland and tropical agricultural methane emissions, the likely major contributors to growth, may be their responses to meteorological change.This work was supported by the UK Natural Environment Research Council projects NE/N016211/1 The Global Methane Budget, NE/M005836/1 Methane at the edge, NE/K006045/1 The Southern Methane Anomaly and NE/I028874/1 MAMM. We thank the UK Meteorological Office for flask collection and hosting the continuous measurement at Ascension, the Ascension Island Government for essential support, and Thumeka Mkololo for flask collection in Cape Tow