Incremental events in the construction of sambaquis, southeastern Santa Catarina.

Moundbuilding is a cross-cultural phenomenon of nearly world-wide scope. In this article some of the moundbuilding processes related to the sambaquis (shellmounds) from the coast of Santa Catarina State, Brasil, are examined, focusing on field research at the sambaqui Jaboticabeira II. By means of analysing the mounding up processes at that site, attention is drawn to its social and demographic corollaries, which speak of considerable social elaboration and territorial permanence in time.A construção de cômoros artificiais (mounds) é um fenômeno de amplo alcance em termos globais. Neste artigo são examinados alguns dos processos responsáveis pela construção destas estruturas no litoral sul de Santa Catarina, tomando-se como referência os trabalhos realizados no sambaqui Jaboticabeira II, município de Jaguaruna. Além da análise dos processos envolvidos na construção daquele sambaqui, procura-se chamar a atenção para os aspectos sociais e demográficos destes mesmos processos, evidenciando um sistema regional de considerável complexidade social e duração cronológica

Biofilm structures (EPS and bacterial communities) in drinking water distribution systems are conditioned by hydraulics and influence discolouration

High-quality drinking water from treatment works is degraded during transport to customer taps through the Drinking Water Distribution System (DWDS). Interactions occurring at the pipe wall-water interface are central to this degradation and are often dominated by complex microbial biofilms that are not well understood. This study uses novel application of confocal microscopy techniques to quantify the composition of extracellular polymeric substances (EPS) and cells of DWDS biofilms together with concurrent evaluation of the bacterial community. An internationally unique, full-scale, experimental DWDS facility was used to investigate the impact of three different hydraulic patterns upon biofilms and subsequently assess their response to increases in shear stress, linking biofilms to water quality impacts such as discolouration. Greater flow variation during growth was associated with increased cell quantity but was inversely related to EPS-to-cell volume ratios and bacterial diversity. Discolouration was caused and EPS was mobilised during flushing of all conditions. Ultimately, biofilms developed under low-varied flow conditions had lowest amounts of biomass, the greatest EPS volumes per cell and the lowest discolouration response. This research shows that the interactions between hydraulics and biofilm physical and community structures are complex but critical to managing biofilms within ageing DWDS infrastructure to limit water quality degradation and protect public health

Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.We would like to thank the EPSRC (SVL, grant nº EP/K0099494/1 and nº EP/K039520/1) for financial support.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ml500507v

Structural Analysis and Development of Notum Fragment Screening Hits

The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development

Effect of aggregation on thermal conduction in colloidal nanofluids

Using effective medium theory we demonstrate that the thermal conductivity of nanofluids can be significantly enhanced by the aggregation of nanoparticles into clusters. The enhancement is based purely on conduction and does not require a novel mechanism. Predictions of the effective medium theory are in excellent agreement with detailed numerical calculations on model nanofluids involving fractal clusters and show the importance of cluster morphology on thermal conductivity enhancements

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets

The recent growth history of the Fornax Cluster derived from simultaneous sloshing and gas stripping: Simulating the infall of NGC 1404

We derive the recent growth history of the Fornax Cluster, in particular the recent infall of the giant elliptical galaxy NGC 1404. We show, using a simple cluster minor merger simulation tailored to Fornax and NGC 1404, that a second or more likely third encounter between the two reproduces all the main merger features observed in both objects; we firmly exclude a first infall scenario. Our simulations reveal a consistent picture: NGC 1404 passed by NGC 1399 about 1.1–1.3 Gyr ago from the northeast to the southwest and is now almost at the point of its next encounter from the south. This scenario explains the sloshing patterns observed in Fornax—a prominent northern cold front and an inner southern cold front. This scenario also explains the truncated atmosphere, the gas-stripping radius of NGC 1404, and its faint gas tail. Independent of the exact history, we can make a number of predictions. A detached bow shock south of NGC 1404 should exist, which is a remnant of the galaxy's previous infall at a distance from NGC 1404 between 450 and 750 kpc with an estimated Mach number between 1.3 and 1.5. The wake of NGC 1404 also lies south of the galaxy with enhanced turbulence and a slight enhancement in metallicity compared to the undisturbed regions of the cluster. Southwest of NGC 1404, there is likely evidence of old turbulence originating from the previous infall. No scenario predicts enhanced turbulence outside of the cold front northwest of the cluster center

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (l-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS model mice lacking maternal Ube3a (Ube3am–/p+ mice) exhibit behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, Ube3am–/p+ mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of l-DOPA therapy in patients with AS

Creative methods: problematics for inquiry and pedagogy in health and social care

This article provides an overview of initial discussions emerging from the Creative Methods Network, an informal organisation concerned with the use of the creative arts in research, teaching and practice in health and social care. Key issues are presented and contextualised with regard to the current conditions in which health and social care research and education is practised. Our own discussions have come to question the seeming dominance of governance within professional education programmes in which there is a primary focus on developing technical skill and capacity. Such governance often extends itself to the measurement of the implementation of these technical skills and this is set against concerns about the absence of creativity and the humanities in the educational programmes of caring for human beings. Consequently, the article reflects a view that the use of the creative arts and humanities in the education of the human caring professions is being eroded away in favour of technical-rational reasoning. It is argued that this then presents an important problem manifested in an emphasis on established and quantifiable knowledge transfer which inhibits other forms of knowledge generation. For the purposes of this discussion we have viewed this problem through the lenses offered by Foucault and Bourdieu