The Daughterless N-terminus directly mediates synergistic interactions with Notch transcription complexes via the SPS+A DNA transcription code

BACKGROUND: Cell-specific expression of a subset of Enhancer of split (E(spl)-C) genes in proneural clusters is mediated by synergistic interactions between bHLH A (basic Helix-Loop-Helix Activator) and Notch-signalling transcription complex (NTC) proteins. For a some of these E(spl)-C genes, such as m8, these synergistic interactions are programmed by an "SPS+A" transcription code in the cis-regulatory regions. However, the molecular mechanisms underlying this synergistic interaction between NTCs and proneural bHLH A proteins are not fully understood. FINDINGS: Using cell transcription assays, we show that the N-terminal region of the Daughterless (Da) bHLH A protein is critical for synergistic interactions with NTCs that activate the E(spl)-C m8 promoter. These assays also show that this interaction is dependent on the specific inverted repeat architecture of Suppressor of Hairless (Su(H)) binding sites in the SPS+A transcription code. Using protein-protein interaction assays, we show that two distinct regions within the Da N-terminus make a direct physical interaction with the NTC protein Su(H). Deletion of these interaction domains in Da creates a dominant negative protein that eliminates NTC-bHLH A transcriptional synergy on the m8 promoter. In addition, over-expression of this dominant negative Da protein disrupts Notch-mediated lateral inhibition during mechanosensory bristle neurogenesis in vivo. CONCLUSION: These findings indicate that direct physical interactions between Da-N and Su(H) are critical for the transcriptional synergy between NTC and bHLH A proteins on the m8 promoter. Our results also indicate that the orientation of the Su(H) binding sites in the SPS+A transcription code are critical for programming the interaction between Da-N and Su(H) proteins. Together, these findings provide insight into the molecular mechanisms by which the NTC synergistically interacts with bHLH A proteins to mediate Notch target gene expression in proneural clusters

Reviews

The following publications have been reviewed by the mentioned authors;Design: Science: Method by R. Jacques and J. A. Powell, reviewed by Sydney GregoryAfrican Textiles and Dyeing Techniques by Claire Polakoff, reviewed by Dorothea KayThe Complete Calligrapher by Fredrick Wong, reviewed by John LancasterSacred Calligraphy of the East by John Stevens, reviewed by John LancasterSchool Crafts - A Folio of Ideas by the Educational Insitutte of Design, Craft and Technology, reviewed by J. W. ThompsonDesign Briefs by the Educational Insitutte of Design, Craft and Technology, reviewed by J. W. ThompsonA Further Portfolio of Ideas by the Educational Insitutte of Design, Craft and Technology, reviewed by J. W. ThompsonThe Medieval Monastery, Five Shropshire Monasteries by the Department of Education, University of Keele, reviewed by Nigel HallProjects and Designs in Metalwork by Ian Punter, reviewed by Ray BlandColor Science for Lighting the Stage by W. B. Warfel and W. R. Klappert, reviewed by A. VargoScottish Technical Education Modules reviewed by John Cav

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells

Geochemistry and related studies of Clyde Estuary sediments

Geochemical and related studies have been made of near-surface sediments from the River Clyde estuary and adjoining areas, extending from Glasgow to the N, and W as far as the Holy Loch on the W coast of Scotland, UK. Multibeam echosounder, sidescan sonar and shallow seismic data, taken with core information, indicate that a shallow layer of modern sediment, often less than a metre thick, rests on earlier glacial and post-glacial sediments. The offshore Quaternary history can be aligned with onshore sequences, with the recognition of buried drumlins, settlement of muds from quieter water, probably behind an ice dam, and later tidal delta deposits. The geochemistry of contaminants within the cores also indicates shallow contaminated sediments, often resting on pristine pre-industrial deposits at depths less than 1 m. The distribution of different contaminants with depth in the sediment, such as Pb (and Pb isotopes), organics and radionuclides, allow chronologies of contamination from different sources to be suggested. Dating was also attempted using microfossils, radiocarbon and 210Pb, but with limited success. Some of the spatial distribution of contaminants in the surface sediments can be related to grain-size variations. Contaminants are highest, both in absolute terms and in enrichment relative to the natural background, in the urban and inner estuary and in the Holy Loch, reflecting the concentration of industrial activity

"The End of Immortality!" Eternal Life and the Makropulos Debate

Responding to a well-known essay by Bernard Williams, philosophers (and a few theologians) have engaged in what I call “the Makropulos debate,” a debate over whether immortality—“living forever”—would be desirable for beings like us. Lacking a firm conceptual grounding in the religious contexts from which terms such as “immortality” and “eternal life” gain much of their sense, the debate has consisted chiefly in a battle of speculative fantasies. Having presented my four main reasons for this assessment, I examine an alternative and neglected conception, the idea of eternal life as a present possession, derived in large part from Johannine Christianity. Without claiming to argue for the truth of this conception, I present its investigation as exemplifying a conceptually fruitful direction of inquiry into immortality or eternal life, one which takes seriously the religious and ethical surroundings of these concepts

Neglected diseases of neglected populations: Thinking to reshape the determinants of health in Latin America and the Caribbean

BACKGROUND: People living in poverty throughout the developing world are heavily burdened with neglected communicable diseases and often marginalized by the health sector. These diseases are currently referred to as Neglected Diseases of Neglected Populations. The neglected diseases create social and financial burdens to the individual, the family, the community, and the nation. DISCUSSION: Numerous studies of successful individual interventions to manage communicable disease determinants in various types of communities have been published, but few have applied multiple interventions in an integrated, coordinated manner. We have identified a series of successful interventions and developed three hypothetical scenarios where such interventions could be applied in an integrated, multi-disease, inter-programmatic, and/or inter-sectoral approach for prevention and control of neglected diseases in three different populations: a slum, an indigenous community, and a city with a mix of populations. SUMMARY: The objective of this paper is to identify new opportunities to address neglected diseases, improve community health and promote sustainable development in neglected populations by highlighting examples of key risk and protective factors for neglected diseases which can be managed and implemented through multi-disease-based, integrated, inter-programmatic, and/or inter-sectoral approaches. Based on a literature review, analysis and development of scenarios we visualize how multiple interventions could manage multiple disease problems and propose these as possible strategies to be tested. We seek to stimulate intra- and inter-sectoral dialogue which will help in the construction of new strategies for neglected diseases (particularly for the parasitic diseases) which could benefit the poor and marginalized based on the principle of sustainability and understanding of key determinants of health, and lead to the establishment of pilot projects and activities which can contribute to the achievement of the Millennium Development Goals

RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery