Sequence analysis of the cupin gene family in Synechocystis PCC6803

The recently described cupin superfamily of proteins includes the germin and germinlike proteins, of which the cereal oxalate oxidase is the best characterized. This superfamily also includes seed storage proteins, in addition to several microbial enzymes and proteins with unknown function. All these proteins are characterized by the conservation of two central motifs, usually containing two or three histidine residues presumed to be involved with metal binding in the catalytic active site. The present study on the coding regions of Synechocystis PCC6803 identifies a previously unknown group of 12 related cupins, each containing the characteristic two-motif signature. This group comprises 11 single-domain proteins, ranging in length from 104 to 289 residues, and includes two phosphomannose isomerases and two epimerases involved in cell wall synthesis, a member of the pirin group of nuclear proteins, a possible transcriptional regulator, and a close relative-of a cytochrome c551 from Rhodococcus. Additionally, there is a duplicated, two-domain protein that has close similarity to an oxalate decarboxylase from the fungus Collybia velutipes and that is a putative progenitor of the storage proteins of land plants

Elevated temperature envelope forming

Elevated temperature envelope forming includes enclosing a part blank and form tool within an envelope sealed against the atmosphere, heat treating the combination while forming pressure holds the envelope and part against the form tool, and allowing part cool down to occur in an inert atmosphere with forming pressure removed. The forming pressure is provided by evacuating the envelope and may be aided by differential force applied between the envelope and the form tool

TNF- α Autocrine Feedback Loops in Human Monocytes:The Pro- and Anti-Inflammatory Roles of the TNF- α Receptors Support the Concept of Selective TNFR1 Blockade in Vivo

Selective TNFR1 blockade in inflammatory diseases is emerging as a clinical strategy. We studied the roles of the two TNF-α receptors, TNFR1 and TNFR2, in human monocytes, the principal producer of TNF-α and central to many TNF-α driven diseases. We hypothesised that TNF-α has pro- and anti-inflammatory effects on monocytes, occurring differentially via TNFR1 and TNFR2. Monocytes were isolated from healthy human subjects and exposed to LPS, plus/minus the addition of blocking antibodies to TNF-α or its receptors. Pro- and anti-inflammatory cytokine production was quantified using real-time PCR and ELISAs. Cell surface expression of TNFR1/2 was measured by flow cytometry. We demonstrated that monocytes vary in the expression patterns of TNFR1 and TNFR2. Autocrine binding of TNF-α led to sustained upregulation of proinflammatory cytokines via TNFR1. In contrast, autocrine binding via TNFR2 upregulated the anti-inflammatory cytokine, IL-10, without proinflammatory effect. TNFR2 was responsible for binding soluble TNF-α secreted by monocytes, clearing the cytokine from the pericellular environment. TNFR1 blockade did not change the cell surface expression of TNFR2, leaving this receptor free to upregulate IL-10. These novel results support the concept of selective TNFR1 blockade in vivo in order that positive anti-inflammatory effects of TNF-α can be retained via TNFR2 ligation

Exploring access to end of life care for ethnic minorities with end stage kidney disease through recruitment in action research

BACKGROUND: Variation in provision of palliative care in kidney services and practitioner concerns to provide equitable access led to the development of this study which focussed on the perspectives of South Asian patients and their care providers. As people with a South Asian background experience a higher risk of Type 2 Diabetes (T2DM) and end stage kidney failure (ESKF) compared to the majority population but wait longer for a transplant, there is a need for end of life care to be accessible for this group of patients. Furthermore because non English speakers and people at end of life are often excluded from research there is a dearth of research evidence with which to inform service improvement. This paper aims to explore issues relating to the process of recruitment of patients for a research project which contribute to our understanding of access to end of life care for ethnic minority patients in the kidney setting. METHODS: The study employed an action research methodology with interviews and focus groups to capture and reflect on the process of engaging with South Asian patients about end of life care. Researchers and kidney care clinicians on four NHS sites in the UK recruited South Asian patients with ESKF who were requiring end of life care to take part in individual interviews; and other clinicians who provided care to South Asian kidney patients at end of life to take part in focus groups exploring end of life care issues. In action research planning, action and evaluation are interlinked and data were analysed with emergent themes fed back to care providers through the research cycle. Reflections on the process of patient recruitment generated focus group discussions about access which were analysed thematically and reported here. RESULTS: Sixteen patients were recruited to interview and 45 different care providers took part in 14 focus groups across the sites. The process of recruiting patients to interview and subsequent focus group data highlighted some of the key issues concerning access to end of life care. These were: the identification of patients approaching end of life; and their awareness of end of life care; language barriers and informal carers' roles in mediating communication; and contrasting cultures in end of life kidney care. CONCLUSIONS: Reflection on the process of recruitment in this action research study provided insight into the complex scenario of end of life in kidney care. Some of the emerging issues such as the difficulty identifying patients are likely to be common across all patient groups, whilst others concerning language barriers and third party communication are more specific to ethnic minorities. A focus on South Asian ethnicity contributes to better understanding of patient perspectives and generic concepts as well as access to end of life kidney care for this group of patients in the UK. Action research was a useful methodology for achieving this and for informing future research to include informal carers and other ethnic groups.Peer reviewedFinal Published versio

Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib.

BackgroundTransforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib.MethodsThis phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored.ResultsThe study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036).ConclusionsConsistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results

Evolving information systems: meeting the ever-changing environment

To meet the demands of organizations and their ever-changing environment, information systems are required which are able to evolve to the same extent as organizations do. Such a system has to support changes in all time-and application-dependent aspects. In this paper, requirements and a conceptual framework for evolving information systems are presented. This framework includes an architecture for such systems and a revision of the traditional notion of update. Based on this evolutionary notion of update (recording, correction and forgetting) a state transition-oriented model on three levels of abstraction (event level, recording level, correction level) is introduced. Examples are provided to illustrate the conceptual framework for evolving information systems

Dangerous liaisons: A ‘Big Four’ framework that provides a ‘hint’ to understanding an adversary’s strategy for influence.

Beliefs, attitudes and behaviour can be influenced in myriad ways. History has consistently demonstrated the struggle between protagonist and antagonist to win over ‘the people’, often through the simultaneous promotion and destruction of places, icons, myths, symbols and stories. Neil Verrall, Mark Dunkley and Toby Gane, three army reserve officers, and Richard Byrne, an independent geographer, describe four interconnected ways in which hostile state actors or non-state terrorist groups might attempt to influence their target audiences as part of strategy

Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study

BACKGROUND: Delays in the diagnosis of children with fragile X syndrome (FXS) suggest the possibility of newborn screening as a way to identify children earlier. However, FXS does not have a proven treatment that must be provided early, and ethical concerns have been raised about the detection of infants who are carriers. This article summarizes major findings from a multisite, prospective, longitudinal pilot screening study. METHODS: Investigators in North Carolina, California, and Illinois collaborated on a study in which voluntary screening for FXS was offered to parents in 3 birthing hospitals. FXS newborn screening was offered to >28 000 families to assess public acceptance and determine whether identification of babies resulted in any measurable harms or adverse events. Secondary goals were to determine the prevalence of FMR1 carrier gene expansions, study the consent process, and describe early development and behavior of identified children. RESULTS: A number of publications have resulted from the project. This article summarizes 10 "lessons learned" about the consent process, reasons for accepting and declining screening, development and evaluation of a decision aid, prevalence of carriers, father participation in consent, family follow-up, and maternal reactions to screening. CONCLUSIONS: The project documented public acceptance of screening as well as the challenges inherent in obtaining consent in the hospital shortly after birth. Collectively, the study provides answers to a number of questions that now set the stage for a next generation of research to determine the benefits of earlier identification for children and families