A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.     

Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition.

In a longitudinal study of HIV seropositive patients, there were fluctuations in the specificity of cytotoxic T cells for the virus. This was matched by variability in proviral gag DNA epitope sequences in the lymphocytes of these patients. Some of these viral variants are not recognized by autologous T cells. Accumulation of such mutations in T-cell antigenic targets would provide a mechanism for immune escape.     

Phase transitions in the assembly of multivalent signalling proteins

Cells are organized on length scales ranging from ?ngstr?m to micrometres. However, the mechanisms by which ?ngstr?m-scale molecular properties are translated to micrometre-scale macroscopic properties are not well understood. Here we show that interactions between diverse synthetic, multivalent macromolecules (including multi-domain proteins and RNA) produce sharp liquid-liquid-demixing phase separations, generating micrometre-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein called neural Wiskott-Aldrich syndrome protein (N-WASP) interacting with its established biological partners NCK and phosphorylated nephrin, the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.     

Systemic Research Practices Towards the Development of an Eco-Community in Vietnam: some Joint Post-Facto Reflections

In this article we discuss how an interdisciplinary research team partnered with a variety of stakeholders concerned with and/or affected by the impacts of climate change in the Red River Delta of Vietnam. The research, undertaken from 2016 to 2018, drew upon a wide range of methods to investigate systemically these impacts – with a view to the research inputting into the development of (more) sustainable ways of living. The research solicited various accounts of the experience of climate change in the community, set up learning processes in community meetings, and created an interface with government officials positioned at commune, district, provincial, and national levels. The intention was to offer support towards developing a learning process (broadly defined as including learnings/systemic inquiry across organizational levels of the society) to pursue options for sustainable living. The article offers our post-facto reflections which render more explicit (to ourselves and for the benefit of audiences) how the research team, with Hoang as lead researcher, facilitated the inquiry process towards developing a synthesis which underscored the assets for resilience to climate change and supported interventions to strengthen such (defined) assets.

     

T-cell signal transduction and the role of protein kinase C

The T lymphocyte has a vital part to play in maintaining the host response to bacterial and viral infection and also appears to play a key pathological role in autoimmune diseases such as rheumatoid arthritis. In this review, we summarize the signalling pathways which trigger antigen-driven T-cell proliferation and examine the evidence which suggests that protein kinase C (PKC) is fundamental to this process. Finally, we discuss the therapeutic potential that PKC inhibitors may have in the treatment of autoimmune disease. Received 31 March 1998; received after revision 19 May 1998; accepted 19 May 1998     

Proximate humid and dry regions in Jupiter's atmosphere indicate complex local meteorology

Models of Jupiter's formation and structure predict that its atmosphere is enriched in oxygen, relative to the Sun, and that consequently water clouds should be present globally near the 5-bar pressure level. Past attempts to confirm these predictions have led to contradictory results; in particular, the Galileo probe revealed a very dry atmosphere at the entry site, with no significant clouds at depths exceeding the 2-bar level. Although the entry site was known to be relatively cloud-free, the contrast between the observed local dryness and the expected global wetness was surprising. Here we analyse near-infrared (around 5 microm) observations of Jupiter, a spectral region that can reveal the water vapour abundance and vertical cloud structure in the troposphere. We find that humid and extremely dry regions exist in close proximity, and that some humid regions are spatially correlated with bright convective clouds extending from the deep water clouds to the visible atmosphere.     

Reversal of the net dinitrogen gas flux in coastal marine sediments

The flux of nitrogen from land and atmosphere to estuaries and the coastal ocean has increased substantially in recent decades. The observed increase in nitrogen loading is caused by population growth, urbanization, expanding water and sewer infrastructure, fossil fuel combustion and synthetic fertilizer consumption. Most of the nitrogen is removed by denitrification in the sediments of estuaries and the continental shelf, leading to a reduction in both cultural eutrophication and nitrogen pollution of the open ocean. Nitrogen fixation, however, is thought to be a negligible process in sub-tidal heterotrophic marine systems. Here we report sediment core data from Narragansett Bay, USA, which demonstrate that heterotrophic marine sediments can switch from being a net sink to being a net source of nitrogen. Mesocosm and core incubation experiments, together with a historic data set of mean annual chlorophyll production, support the idea that a climate-induced decrease in primary production has led to a decrease in organic matter deposition to the benthos and the observed reversal of the net sediment nitrogen flux. Our results suggest that some estuaries may no longer remove nitrogen from the water column. Instead, nitrogen could be exported to the continental shelf and the open ocean and could shift the effect of anthropogenic nitrogen loading beyond the immediate coastal zone.     

HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides

Current candidate vaccines fail to protect primates against challenge with human immunodeficiency virus (HIV) in the presence of antibody responses; this underlines the importance of studying cell-mediated immunity to HIV and identifying specific epitopes that stimulate cytotoxic T lymphocytes (CTL). Using a recombinant vaccinia virus to express the gag protein of HIV-1 we found HLA class-I-restricted gag-specific CTL in thirteen out of fifteen healthy HIV seropositive patients. We then used short synthetic peptides in the lysis assay to screen for gag CTL epitopes. In one patient we have identified a peptide in p24 that is recognized by CTL in association with HLA-B27. This peptide, and further peptide sequences defined by these methods, could be incorporated in vaccines designed to induce cell-mediated immunity against HIV.