A geochemical traverse across the North Chilean Andes

A transect across the Andean cordillerâ at latitude 22°S in Chile is investigated using geochemical and geochronological techniques. The oldest rocks in the region are the Limon Verde schists, which yield a Rb-Sr whole rock age of 251+50 Ma. This is considered to reflect resetting by the intrusion of the adjacent Limon Verde pluton. TNDDM ages range from 913 - 1308 Ma indicating the presence of old lithosphere on the western flanks of the Andes. The Limon Verde pluton gives a whole rock Rb-Sr age of 266+42 Ma (e = iSr = 26.5). Its Sr and Nd isotopes are slightly enriched relative to 'bulk Earth' and derivation from isotopically enriched mantle or equilibration of the whole, more depleted magma with a crustal melt prior to high level fractionation is favoured. Rhyolitic lavas of the Cerro Crespo Formation yield a whole rock Rb-Sr age -of 233+36 Ma (e iSR = 40.2). Their petrogenesis is considered to be similar to that of the Limon Verde pluton. The La Negra Formation outcrops in the Cordillera de la Costa, and marks the start of the 'Andean Orogeny' in this transect. The lavas yield a whole rock Rb-Sr age of 186+14 Ma (e iSR = -18.8). They are mainly plagioclase phyric, high K basaltic andesites exhibiting tholeiitic fractionation trends. Sr and Nd isotope systematics indicate derivation from a depleted mantle source. More than 80% of Sr, K, Rb, Ba and Th, and less than 60% Ce, Nd, P and Sm are introduced as the subduction zone component. Plots of Hf/LILE and Hf/HFSE against these proportions yield information regarding the elemental concentrations in the mantle prior to the addition of the Subduction zone component. This mantle had e 1Nd ~ +10, and the subduction zone component had eiNd ~ -2. To satisfy trace element criteria, the addition of the subduction zone component must have been a multistage process. The La Negra Formation is considered to have been erupted through fissures in an ensialic back, arc basin. Jurassic plutons in the Cordillera de la Costa yield ages between 158 - 154 Ma. Parts of the Tocopilla pluton experienced late-stage alkali metasomatism resulting in the formation of "monzonites". Trace element and isotopic differences between the plutons are due to derivation from a heterogeneous, isotopically depleted mantle source. Jurassic marine and lower Cretaceous continental sedimentation around Cerritos Bayos was succeeded by the lavas of the Indio Muerto Formation. Immobile inter HFSE ratios suggest derivation from a variety of mantle sources: Nd isotope data imply that significant crustal contamination may have occurred. The Augusta Victoria Formation gives an age of 105+19 Ma (e1Sr = -4.3). Two magma types are present, the high K group being derived from a more trace element enriched source than the low K group. The Cerro Negro Formation, which is composed mainly of tuffs with isolated lavas, was derived from an isotopically depleted source within the garnet stability field. Emplacement of plutons during the Cretaceous occurred at 100 Ma in the Cerros de Montecristo and at Cerritos Bayos, at 79 Ma in the Pampa Negra and at 66 Ma at Cerro Colorado. Whilst Cerro Colorado is highly potassic, the other plutons follow calcalkaline trends. The Cerritos Bayos pluton has been affected by late-stage alkali metasomatism and post consolidation silicification which has disturbed much of its geochemistry. Isotope systematics suggest that the Cerros de Montecristo, Cerritos Bayos and Cerro Colorado plutons have tapped isotopically distinct sources, whereas the Pampa Negra pluton may have experienced complex crustal interaction. The El Abra pluton yields an age of 39+.2 Ma (e1Sr -2). There is no evidence to indicate that it has suffered significant crustal contamination. Tertiary volcanics between 15.2 and 2.5 Ma all have slightly enriched isotopic characteristics. Their TNdDM ages range from 798 - 1151 Ma, again implying that the Western Cordillera is underlain by old lithosphere. Recent basic monogenetic centres also have enriched isotopic characteristics and subduction-related trace element geochemistry. An alkali basalt from Bolivia, however, is unrelated to subduction and has more depleted isotope systematics; its source is probably below the continental lithosphere. Revised and additional Sr and Nd isotope data for San Pedro and Ecuador are presented. There has been a general eastwards migration in the locus of magmatism since the Jurassic. Isotope data show that younger, more easterly units tap progressively less depleted sources, and that to the east of the Rio Loa these are enriched relative to 'bulk Earth'. Trace element data indicate that the proportion of the subduction zone component in volcanic rocks decreases from the Jurassic - Recent. Variations in the subduction zone component and progressively increasing degrees of crustal contamination of depleted mantle derived magmas are not thought to be responsible for the observed isotopic and trace element variations. Instead, as the locus of magmatism has migrated eastwards it has tapped more trace element and isotopically enriched, and probably older mantle source regions. The increase in crustal thickness since the Miocene may be attributable to tectonic underthrusting of the continental margin. The thickening crust promotes the likelihood of crustal anatexis and contamination. This contamination, however, operates on magmas derived from old, enriched mantle sources

The development of sialidase inhibitors using structure-based drug design

The sialidases/neuraminidases represent a family of enzymes whose function is important in the pathogenicity of bacteria and the virulence of influenza. Relenza and Tamiflu represent two drugs that were developed using structure-based drug design (SBDD) and computational-assisted drug design (CADD). These drugs target the active site of the influenza neuraminidase A and B (GH-34 family). Sialidases in the GH-33 family could represent novel drug targets for the treatment of bacterial or parasitic infection. SBDD was employed to develop chemical tools of two GH-33 sialidases, NanB and TcTS. NanB is a potential drug target for S. pneumoniae. The chemical tool developed for NanB follows on from work within the Taylor and Westwood research groups, in which a molecule of CHES and a glycerol were found serendipitously bound within a water channel at an allosteric site. Using this information as a basis for SBDD an allosteric inhibitor of NanB, Optactin was developed. Within this work, synthesis of this inhibitor was achieved and optimised. Optactin was then modified to improve potency. This proceeded through an amide analogue and addition of an arene resulting in a mid- micromolar inhibitor (IC₅₀: 55.4±2.5 µM). Addition of polar substituents improved potency further resulting in a low micromolar inhibitor of NanB, Optactamide (IC₅₀: 3.0±1.7 µM). Application of this tool in vitro demonstrated that NanB and NanA have a role in invasion of S. pneumoniae into lung epithelial cells. TcTS is a potential drug target for the treatment of Chagas disease. A CADD approach using a fragment library was unsuccessful at identifying an allosteric inhibitor of TcTS despite structural similarity with NanB. A re-task of the CADD approach towards the active site was successful in identifying an inhibitor of TcTS and a fragment useful for further development. This work sets the groundwork for the development of a chemical tool targeting TcTS

The medium-term sustainability of organisational innovations in the national health service

Background: There is a growing recognition of the importance of introducing new ways of working into the UK's National Health Service (NHS) and other health systems, in order to ensure that patient care is provided as effectively and efficiently as possible. Researchers have examined the challenges of introducing new ways of working-'organisational innovations'-into complex organisations such as the NHS, and this has given rise to a much better understanding of how this takes place-and why seemingly good ideas do not always result in changes in practice. However, there has been less research on the medium-and longer-term outcomes for organisational innovations and on the question of how new ways of working, introduced by frontline clinicians and managers, are sustained and become established in day-to-day practice. Clearly, this question of sustainability is crucial if the gains in patient care that derive from organisational innovations are to be maintained, rather than lost to what the NHS Institute has called the 'improvement-evaporation effect'. Methods: The study will involve research in four case-study sites around England, each of which was successful in sustaining its new model of service provision beyond an initial period of pilot funding for new genetics services provided by the Department of Health. Building on findings relating to the introduction and sustainability of these services already gained from an earlier study, the research will use qualitative methods-in-depth interviews, observation of key meetings, and analysis of relevant documents-to understand the longer-term challenges involved in each case and how these were surmounted. The research will provide lessons for those seeking to sustain their own organisational innovations in wide-ranging clinical areas and for those designing the systems and organisations that make up the NHS, to make them more receptive contexts for the sustainment of innovation. Discussion: Through comparison and contrast across four sites, each involving different organisational innovations, different forms of leadership, and different organisational contexts to contend with, the findings of the study will have wide relevance. The research will produce outputs that are useful for managers and clinicians responsible for organisational innovation, policy makers and senior managers, and academics

Higher Education Opportunities for Gypsy Roma Traveller Young People in West Yorkshire

A research report commissioned by Go Higher West Yorkshire to identify the barriers and solutions to access to Higher Education for young Gypsies, Travellers and Roma in the uni-connect area

Identifying structural brain markers of resilience to adversity in young people using voxel-based morphometry

There is increasing evidence that resilience in youth may have a neurobiological basis. However, the existing literature lacks a consistent way of operationalizing resilience, often relying on arbitrary judgments or narrow definitions (e.g., not developing PTSD) to classify individuals as resilient. Therefore, this study used data-driven, continuous resilience scores based on adversity and psychopathology to investigate associations between resilience and brain structure in youth. Structural MRI data from 298 youth aged 9–18 years (M$_{age}$ = 13.51; 51% female) who participated in the European multisite FemNAT-CD study were preprocessed using SPM12 and analyzed using voxel-based morphometry. Resilience scores were derived by regressing data on adversity exposure against current/lifetime psychopathology and quantifying each individual’s distance from the regression line. General linear models tested for associations between resilience and gray matter volume (GMV) and examined whether associations between resilience and GMV differed by sex. Resilience was positively correlated with GMV in the right inferior frontal and medial frontal gyri. Sex-by-resilience interactions were observed in the middle temporal and middle frontal gyri. These findings demonstrate that resilience in youth is associated with volume in brain regions implicated in executive functioning, emotion regulation, and attention. Our results also provide evidence for sex differences in the neurobiology of resilience

The capacity of the fecal microbiota from Malawian infants to ferment resistant starch

In Low and Middle-Income Countries (LMIC), weaning is associated with environmentally acquired and inflammation-associated enteric disorders. Dietary intake of high amylose maize starch (HAMS) can promote commensal fermentative bacteria and drive the production of short chain fatty acids (SCFAs). By stabilizing commensal gut microbiology, and stimulating the production of anti-inflammatory metabolites, HAMS supplementation might therefore influence enteric health. However, the extent to which the gut microbiota of LMIC infants are capable of fermenting HAMS is unclear. We assessed the capacity of the fecal microbiota from pre-weaning and weaning Malawian infants to ferment HAMS and produce SCFAs using an in vitro fermentation model. Fecal microbiota from both pre-weaning and weaning infants were able to ferment HAMS, as indicated by an increase in bacterial load and total SCFA concentration, and a reduction in pH. All of these changes were more substantial in the weaning group. Acetate production was observed with both pre-weaning and weaning groups, while propionate production was only observed in the weaning group. HAMS fermentation resulted in significant alterations to the fecal microbial community in the weaning group, with significant increases in levels of Prevotella, Veillonella, and Collinsella associated with propionate production. In conclusion, fecal microbiota from Malawian infants before and during weaning has the capacity to produce acetate through HAMS fermentation, with propionate biosynthetic capability appearing only at weaning. Our results suggest that HAMS supplementation might provide benefit to infants during weaning

Identifying cortical structure markers of resilience to adversity in young people using surface-based morphometry

Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition