Structure-Phenotype Correlations of Human CYP21A2 Mutations in Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) is a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by adrenal cortex. The predominant causes of the disorder are mutations in the CYP21A2 gene that encodes a Cytochrome P450 21-hydroxylase enzyme, which is central to steroidogenesis. The severity of the disease depends upon the extent of impaired enzymatic activity and can be classified under severe Classical form or the mild Non-Classical form, Molecular characterisation of CYP21A2 mutations can be used to predict clinical phenotype and disease severity based upon changes it brings in 21-hydroxylase enzyme structure. A humanized model of CYP21A2 has been used to map and investigate the structural role of all known disease-causing mutations. A structural explanation of clinical manifestation allows us to put forward criteria that might allow the prediction of clinical severity of the disease.

A theoretical study of the effects of lithium intercalation on the electronic structure of TiS

The band structure of the intercalation complex of LiTiS has been computed using a semi-empirical tight-binding method and this is compared with the results of a revised TiS calculation. The results obtained confirm that changes in the basic electrical characteristics of TiS, which occur when it is intercalated with lithium, can be attributed to a rigid-band filling of its lowest unoccupied electron states as has previously been proposed. However, they also suggest that intercalation can act to alter the nature and the dispersion of some of the energy bands in the unintercalated crystal. The bands which are most affected by the process are those which derive from orbitals which have the same symmetry as the lithium 2s orbital, namely, the titanium 4s conduction level and the tightly bound sulphur 3s levels.

Effects of very low birthweight on brain structure in adulthood

Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period. We wished to determine how such early brain lesions affect brain structure in adulthood. Thirty-two VLBW adults (20 female, 12 male) and, 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 3.4). Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space. Images were then warped to a template image in standard space. There was no significant between-group difference in whole brain, greymatter, white matter, or total cerebral spinal fluid (CSF) volumes. However, lateral ventricular volume was significantly increased by 41% in those with VLBW. The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW. Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals. Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter. We conclude that these diffuse abnormalities of grey and white matter are a consequence,of the interaction of perinatal brain injury and ongoing neurodevelopmental processes.

Rapid changes in the level of Kluane Lake in Yukon Territory over the last millennium

The level of Kluane Lake, the largest lake in Yukon Territory, was lower than at present during most of the Holocene. The lake rose rapidly in the late seventeenth century to a level 12 m above present, drowning forest and stranding driftwood on a conspicuous high-stand beach, remnants of which are preserved at the south end of the lake. Kluane Lake fell back to near its present level by the end of the eighteenth century and has fluctuated within a range of about 3 m over the last 50 yr. The primary control on historic fluctuations in lake level is the discharge of Slims River, the largest source of water to the lake. We use tree ring and radiocarbon ages, stratigraphy and sub-bottom acoustic data to evaluate two explanations for the dramatic changes in the level of Kluane Lake. Our data support the hypothesis of Hugh Bostock, who suggested in 1969 that the maximum Little Ice Age advance of Kaskawulsh Glacier deposited large amounts of sediment in the Slims River valley and established the present course of Slims River into Kluane Lake. Bostock argued that these events caused the lake to rise and eventually overflow to the north. The overflowing waters incised the Duke River fan at the north end of Kluane Lake and lowered the lake to its present level. This study highlights the potentially dramatic impacts of climate change on regional hydrology during the Little Ice Age in glacierised mountains. © 2006 University of Washington.

Lake Kumphawapi – an archive of Holocene palaeoenvironmental and palaeoclimatic changes in northeast Thailand

The long-term climatic and environmental history of Southeast Asia, and of Thailand in particular, is still fragmentary. Here we present a new 14C-dated, multi-proxy sediment record (TOC, C/N, CNS isotopes, Si, Zr, K, Ti, Rb, Ca elemental data, biogenic silica) for Lake Kumphawapi, the second largest natural lake in northeast Thailand. The data set provides a reconstruction of changes in lake status, groundwater fluctuations, and catchment run-off during the Holocene. A comparison of multiple sediment sequences and their proxies suggests that the summer monsoon was stronger between c. 9800 and 7000 cal yr BP. Lake status and water level changes around 7000 cal yr BP signify a shift to lower effective moisture. By c. 6500 cal yr BP parts of the lake had been transformed into a peatland, while areas of shallow water still occupied the deeper part of the basin until c. 5400–5200 cal yr BP. The driest interval in Kumphawapi's history occurred between c. 5200 and 3200 cal yr BP, when peat extended over large parts of the basin. After 3200 cal yr BP, the deepest part of the lake again turned into a wetland, which existed until c. 1600 cal yr BP. The observed lake-level rise after 1600 cal yr BP could have been caused by higher moisture availability, although increased human influence in the catchment cannot be ruled out. The present study highlights the use of multiple sediment sequences and proxies to study large lakes, such as Lake Kumphawapi in order to correctly assess the time transgressive response to past changes in hydroclimate conditions. Our new data set from northeast Thailand adds important palaeoclimatic information for a region in Southeast Asia and allows discussing Holocene monsoon variability and ITCZ movement in greater detail.

Pathogenic Yersinia enterocolitica strains increase the outer membrane permeability in response to environmental stimuli by modulating lipopolysaccharide fluidity and lipid A structure

Pathogenic biotypes of Yersinia enterocolitica (serotypes O:3, O:8, O:9, and O:13), but not environmental biotypes (serotypes O:5, O:6, O:7,8, and O:7,8,13,19), increased their permeability to hydrophobic probes when they were grown at pH 5.5 or in EGTA-supplemented (Ca(2+)-restricted) media at 37 degrees C. A similar observation was also made when representative strains of serotypes O:8 and O:5 were tested after brief contact with human monocytes. The increase in permeability was independent of the virulence plasmid. The role of lipopolysaccharide (LPS) in this phenomenon was examined by using Y. enterocolitica serotype O:8. LPS aggregates of bacteria grown in acidic or EGTA-supplemented broth took up more N-phenylnaphthylamine than LPS aggregates of bacteria grown in standard broth and also showed a marked increase in acyl chain fluidity which correlated with permeability, as determined by measurements obtained in the presence of hydrophobic dyes. No significant changes in O-antigen polymerization were observed, but lipid A acylation changed depending on the growth conditions. In standard medium at 37 degrees C, there were hexa-, penta-, and tetraacyl lipid A forms, and the pentaacyl form was dominant. The amount of tetraacyl lipid A increased in EGTA-supplemented and acidic media, and hexaacyl lipid A almost disappeared under the latter conditions. Our results suggest that pathogenic Y. enterocolitica strains modulate lipid A acylation coordinately with expression of virulence proteins, thus reducing LPS packing and increasing outer membrane permeability. The changes in permeability, LPS acyl chain fluidity, and lipid A acylation in pathogenic Y. enterocolitica strains approximate the characteristics in Yersinia pseudotuberculosis and Yersinia pestis and suggest that there is a common outer membrane pattern associated with pathogenicity.

Vegetation changes and human settlement of Easter Island during the last millennia: a multiproxy study of the Lake Raraku sediments

Earlier palynological studies of lake sediments from Easter Island suggest that the island underwent a recent and abrupt replacement of palm-dominated forests by grasslands, interpreted as a deforestation by indigenous people. However, the available evidence is inconclusive due to the existence of extended hiatuses and ambiguous chronological frameworks in most of the sedimentary sequences studied. This has given rise to an ongoing debate about the timing and causes of the assumed ecological degradation and cultural breakdown. Our multiproxy study of a core recovered from Lake Raraku highlights the vegetation dynamics and environmental shifts in the catchment and its surroundings during the late Holocene. The sequence contains shorter hiatuses than in previously recovered cores and provides a more continuous history of environmental changes. The results show a long, gradual and stepped landscape shift from palm-dominated forests to grasslands. This change started c. 450 BC and lasted about two thousand years. The presence of Verbena litoralis, a common weed, which is associated with human activities in the pollen record, the significant correlation between shifts in charcoal influx, and the dominant pollen types suggest human disturbance of the vegetation. Therefore, human settlement on the island occurred c. 450 BC, some 1500 years earlier than is assumed. Climate variability also exerted a major influence on environmental changes. Two sedimentary gaps in the record are interpreted as periods of droughts that could have prevented peat growth and favoured its erosion during the Medieval Climate Anomaly and the Little Ice Age, respectively. At c. AD 1200, the water table rose and the former Raraku mire turned into a shallow lake, suggesting higher precipitation/evaporation rates coeval with a cooler and wetter Pan-Pacific AD 1300 event. Pollen and diatom records show large vegetation changes due to human activities c. AD 1200. Other recent vegetation changes also due to human activities entail the introduction of taxa (e.g. Psidium guajava, Eucalyptus sp.) and the disappearance of indigenous plants such as Sophora toromiro during the two last centuries. Although the evidence is not conclusive, the American origin of V. litoralis re-opens the debate about the possible role of Amerindians in the human colonisation of Easter Island.

Photosynthetic pigments in soils from northern Victoria Land (continental Antarctica) as proxies for soil algal community structure and function

Although soil algae are among the main primary producers in most terrestrial ecosystems of continental Antarctica, there are very few quantitative studies on their relative proportion in the main algal groups and on how their distribution is affected by biotic and abiotic factors. Such knowledge is essential for understanding the functioning of Antarctic terrestrial ecosystems. We therefore analyzed biological soil crusts from northern Victoria Land to determine their pH, electrical conductivity (EC) water content (W), total and organic C (TC and TOC) and total N (TN) contents, and the presence and abundance of photosynthetic pigments. In particular, the latter were tested as proxies for biomass and coarse-resolution community structure. Soil samples were collected from five sites with known soil algal communities and the distribution of pigments was shown to reflect differences in the relative proportions of Chlorophyta, Cyanophyta and Bacillariophyta in these sites. Multivariate and univariate models strongly indicated that almost all soil variables (EC, W, TOC and TN) were important environmental correlates of pigment distribution. However, a significant amount of variation is independent of these soil variables and may be ascribed to local variability such as changes in microclimate at varying spatial and temporal scales. There are at least five possible sources of local variation: pigment preservation, temporal variations in water availability, temporal and spatial interactions among environmental and biological components, the local-scale patchiness of organism distribution, and biotic interactions. (C) 2009 Elsevier Ltd. All rights reserved.

Structure-reactivity Correlations in the catalytic coupling of ethyne over novel bimetallic Pd/Sn catalysts

The structure, thermal stability, and catalytic behavior of a novel highly dispersed silica-supported Pd/Sn catalyst prepared by an organometallic route have been examined by X-ray photoelectron, X-ray diffraction, and X-ray absorption, fine structure spectroscopies, the latter two measurements being carried outwith an in situ reaction cell. Additional reactor measurements were performed on a more Sn-rich catalyst and on a pure Pd catalyst. Varying the temperature of reduction induced large variations in catalytic performance toward ethyne-coupling reactions. These changes are understandable in terms of the destruction of SnO2-like structures surrounding the Pd core, yielding a skin of metallic Sn which subsequently undergoes intermixing with Pd. The overall thermal and catalytic behavior of these highly dispersed materials accords well with the analogous single-crystal model system.

The anatomy of Last Glacial Maximum climate variations in south Westland, New Zealand, derived from pollen records

We present pollen records from three sites in south Westland, New Zealand, that document past vegetation and inferred climate change between approximately 30,000 and 15,000 cal. yr BP. Detailed radiocarbon dating of the enclosing sediments at one of those sites, Galway tarn, provides a more robust chronology for the structure and timing of climate-induced vegetation change than has previously been possible in this region. The Kawakawa/Oruanui tephra, a key isochronous marker, affords a precise stratigraphic link across all three pollen records, while other tie points are provided by key pollen-stratigraphic changes which appear to be synchronous across all three sites. Collectively, the records show three episodes in which grassland, interpreted as indicating mostly cold subalpine to alpine conditions, was prevalent in lowland south Westland, separated by phases dominated by subalpine shrubs and montane-lowland trees, indicating milder interstadial conditions. Dating, expressed as a Bayesian-estimated single 'best' age followed in parentheses by younger/older bounds of the 95% confidence modelled age range, indicates that a cold stadial episode, whose onset was marked by replacement of woodland by grassland, occurred between 28,730 (29,390-28,500) and 25,470 (26,090-25,270) cal. yr BP (years before AD, 1950), prior to the deposition of the Kawakawa/Oruanui tephra. Milder interstadial conditions prevailed between 25,470 (26,090-25,270) and 24,400 (24,840-24,120) cal. yr BP and between 22,630 (22,930-22,340) and 21,980 (22,210-21,580) cal. yr BP, separated by a return to cold stadial conditions between 24,400 and 22,630 cal. yr BP. A final episode of grass-dominated vegetation, indicating cold stadial conditions, occurred from 21,980 (22,210-21,580) to 18,490 (18,670-17,950) cal. yr BP. The decline in grass pollen, indicating progressive climate amelioration, was well advanced by 17,370 (17,730-17,110) cal. yr BP, indicating that the onset of the termination in south Westland occurred sometime between ca 18,490 and ca 17,370 cal. yr BP. A similar general pattern of stadials and interstadials is seen, to varying degrees of resolution but generally with lesser chronological control, in many other paleoclimate proxy records from the New Zealand region. This highly resolved chronology of vegetation changes from southwestern New Zealand contributes to the examination of past climate variations in the southwest Pacific region. The stadial and interstadial episodes defined by south Westland pollen records represent notable climate variability during the latter part of the Last Glaciation. Similar climatic patterns recorded farther afield, for example from Antarctica and the Southern Ocean, imply that climate variations during the latter part of the Last Glaciation and the transition to the Holocene interglacial were inter-regionally extensive in the Southern Hemisphere and thus important to understand in detail and to place into a global context. © 2013 Elsevier Ltd. All rights reserved.

The internal structure of asteroid (25143) Itokawa as revealed by detection of YORP spin-up *’**

Context. Near-Earth asteroid (25143) Itokawa was visited by the Hayabusa spacecraft in 2005, resulting in a highly detailed shape and surface topography model. This model has led to several predictions for the expected radiative torques on this asteroid, suggesting that its spin rate should be decelerating. Aims. To detect changes in rotation rate that may be due to YORP-induced radiative torques, which in turn may be used to investigate the interior structure of the asteroid. Methods. Through an observational survey spanning 2001 to 2013 we obtained rotational lightcurve data at various times over the last five close Earth-approaches of the asteroid. We applied a polyhedron-shape-modelling technique to assess the spin-state of the asteroid and its long term evolution. We also applied a detailed thermophysical analysis to the shape model determined from the Hayabusa spacecraft. Results. We have successfully measured an acceleration in Itokawa's spin rate of dω/dt = (3.54 ± 0.38) × 10 rad day, equivalent to a decrease of its rotation period of ~45 ms year. From the thermophysical analysis we find that the centre-of-mass for Itokawa must be shifted by ~21 m along the long-axis of the asteroid to reconcile the observed YORP strength with theory. Conclusions. This can be explained if Itokawa is composed of two separate bodies with very different bulk densities of 1750 ± 110 kg m and 2850 ± 500 kg m, and was formed from the merger of two separate bodies, either in the aftermath of a catastrophic disruption of a larger differentiated body, or from the collapse of a binary system. We therefore demonstrate that an observational measurement of radiative torques, when combined with a detailed shape model, can provide insight into the interior structure of an asteroid. Futhermore, this is the first measurement of density inhomogeneity within an asteroidal body, that reveals significant internal structure variation. A specialised spacecraft is normally required for this.

Development and validation of Fluid Structure Interaction Methods for an Oscillating Wave Surge Converter

The term fatigue loads on the Oyster Oscillating Wave Surge Converter (OWSC) is used to describe hydrostatic loads due to water surface elevation with quasi-static changes of state. Therefore a procedure to implement hydrostatic pressure distributions into finite element analysis of the structure is desired. Currently available experimental methods enable one to measure time variant water surface elevation at discrete locations either on or around the body of the scale model during tank tests. This paper discusses the development of a finite element analysis procedure to implement time variant, spatially distributed hydrostatic pressure derived from discretely measured water surface elevation. The developed method can process differently resolved (temporal and spatial) input data and approximate the elevation over the flap faces with user defined properties. The structural loads, namely the forces and moments on the body can then be investigated by post processing the numerical results. This method offers the possibility to process surface elevation or hydrostatic pressure data from computational fluid dynamics simulations and can thus be seen as a first step to a fluid-structure interaction model.

The performance of a cathodic protection system in reinforced concrete structure: Monitoring and Service Life Modelling

The use of cathodic protection in reinforced concrete is becoming increasingly common with such systems being installed on a number of structures throughout the United Kingdom and Ireland. However the prescribed design lives (or service life) of each cathodic protection system vary widely. The aim of this project was to assess the effectiveness of a sacrificial anode cathodic protection system and to predict its design life through a series of laboratory based experiments. The experimental plan involved casting a number of slabs which represented a common road bridge structure. The corrosion of the steel within the experimental slabs was then accelerated prior to installation of a cathodic protection system. During the experiment corrosion potential of the steel reinforcement was monitored using half-cell measurement. Additionally the current flow between the cathodic protection system and the steel reinforcement was recorded to assess the degree of protection. A combination of theoretical calculations and experimental results were then collated to determine the design life of this cathodic protection system. It can be concluded that this sacrificial anode based cathodic protection system was effective in halting the corrosion of steel reinforcement in the concrete slabs studied. Both the corrosion current and half-cell potentials indicated a change in passivity for the steel reinforcement once sacrificial anodes were introduced. The corrosion current was observed to be sensitive to the changes to the exposure environment. Based on the experimental variables studied the design life of this sacrificial anode can be taken as 26 to 30 years.

Sea-level changes in Iceland and the influence of the North Atlantic Oscillation during the last half millennium

We present a new, diatom-based sea-level reconstruction for Iceland spanning the last -500 years, and investigate the possible mechanisms driving the sea-level changes. A sea-level reconstruction from near the Icelandic low pressure system is important as it can improve understanding of ocean-atmosphere forcing on North Atlantic sea-level variability over multi-decadal to centennial timescales. Our reconstruction is from Viarhólmi salt marsh in Snæfellsnes in western Iceland, a site from where we previously obtained a 2000-yr record based upon less precise sea-level indicators (salt-marsh foraminifera). The 20th century part of our record is corroborated by tide-gauge data from Reykjavik. Overall, the new reconstruction shows ca0.6m rise of relative sea level during the last four centuries, of which ca0.2m occurred during the 20th century. Low-amplitude and high-frequency sea-level variability is super-imposed on the pre-industrial long-term rising trend of 0.65m per 1000 years. Most of the relative sea-level rise occurred in three distinct periods: AD 1620-1650, AD 1780-1850 and AD 1950-2000, with maximum rates of ~3±2mm/yr during the latter two of these periods. Maximum rates were achieved at the end of large shifts (from negative to positive) of the winter North Atlantic Oscillation (NAO) Index as reconstructed from proxy data. Instrumental data demonstrate that a strong and sustained positive NAO (a deep Icelandic Low) generates setup on the west coast of Iceland resulting in rising sea levels. There is no strong evidence that the periods of rapid sea-level rise were caused by ocean mass changes, glacial isostatic adjustment or regional steric change. We suggest that wind forcing plays an important role in causing regional-scale coastal sea-level variability in the North Atlantic, not only on (multi-)annual timescales, but also on multi-decadal to centennial timescales.

Water structure and chaotropicity: their uses, abuses and biological implications

The concept of "water structure" has been invoked to explain all manner of aqueous phenomena. Here we look at the origins of this tendency to understand solute hydration in terms of structural changes in bulk water, and consider the validity of one particular example: the classification of small solutes as chaotropic or kosmotropic, and the putative relation of this terminology to notions of structure-making and structure-breaking in the solvent. We doubt whether complex phenomena such as Hofmeister and osmolyte effects on macromolecules can be understood simply on the basis of a change in solvent structure. Rather, we argue that chaotropicity, if understood in the original sense, arises from the activities that solutes exert on macromolecular systems, as well as from deviations of solvation water from bulk-like behaviour. If applied judiciously, chaotropicity remains a potent, biologically pertinent parameter useful for classifying and understanding solution phenomena in all types of living system.