Molecular cytogenetic analysis of patients with holoprosencephaly and structural rearrangements of 7q

The holoprosencephaly (HPE) sequence is a malformation complex with abnormal midline cleavage of the embryonic forebrain. HPE is genetically heterogeneous with at least 6 different chromosome regions containing genes involved in the expression of the phenotype. HPE3, recently identified as the human Sonic hedgehog gene, is localized to 7q36. We have used fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) amplification in 5 cell lines from patients with HPE (3 cases), HPE and sacral agenesis (1 case), and microcephaly (1 case) to further define the structural rearrangements of the long arm of chromosome 7 in each case. All cell lines demonstrated loss of material in the critical region of HPE3 at band 7q36, which includes the Sonic hedgehog gene. We report here the analysis of these patient cell lines

A boundary exchange influence on deglacial neodymium isotope records from the deep western Indian Ocean

The use of neodymium (Nd) isotopes to reconstruct past water mass mixing relies upon the quasi-conservative behaviour of this tracer, whereas recent studies in the modern oceans have suggested that boundary exchange, involving the addition of Nd from ocean margin sediments, may be an important process in the Nd cycle. Here we suggest that the relative importance of water mass advection versus boundary exchange can be assessed where the deep western boundary current in the Indian Ocean flows past the Madagascan continental margin; a potential source of highly unradiogenic Nd. Foraminiferal coatings and bulk sediment reductive leachates are used to reconstruct bottom water Nd isotopic composition (εNd) in 8 Holocene age coretops, with excellent agreement between the two methods. These data record spatial variability of ∼4 εNd units along the flow path of Circumpolar Deep Water; εNd≈−8.8 in the deep southern inflow upstream of Madagascar, which evolves towards εNd≈−11.5 offshore northern Madagascar, whereas εNd≈−7.3 where deep water re-circulates in the eastern Mascarene Basin. This variability is attributed to boundary exchange and, together with measurements of detrital sediment εNd, an isotope mass balance suggests a deep water residence time for Nd of ≤400 yr along the Madagascan margin. Considering deglacial changes, a core in the deep inflow upstream of Madagascar records εNd changes that agree with previous reconstructions of the Circumpolar Deep Water composition in the Southern Ocean, consistent with a control by water mass advection and perhaps indicating a longer residence time for Nd in the open ocean away from local sediment inputs. In contrast, sites along the Madagascan margin record offset εNd values and reduced glacial–interglacial variability, underlining the importance of detecting boundary exchange before inferring water mass source changes from Nd isotope records. The extent of Madagascan boundary exchange appears to be unchanged between the Holocene and Late Glacial periods, while a consistent shift towards more radiogenic εNd values at all sites in the Late Glacial compared to the Holocene may represent a muted signal of a change in water mass source or composition

Reactivity of neodymium carriers in deep sea sediments: Implications for boundary exchange and paleoceanography

The dissolved neodymium (Nd) isotopic distribution in the deep oceans is determined by continental weathering inputs, water mass advection, and boundary exchange between particulate and dissolved fractions. Reconstructions of past Nd isotopic variability may therefore provide evidence on temporal changes in continental weathering inputs and/or ocean circulation patterns over a range of timescales. However, such an approach is limited by uncertainty in the mechanisms and importance of the boundary exchange process, and the challenge in reliably recovering past seawater Nd isotopic composition (εNd) from deep sea sediments. This study addresses these questions by investigating the processes involved in particulate–solution interactions and their impact on Nd isotopes. A better understanding of boundary exchange also has wider implications for the oceanic cycling and budgets of other particle-reactive elements. Sequential acid-reductive leaching experiments at pH ∼2–5 on deep sea sediments from the western Indian Ocean enable us to investigate natural boundary exchange processes over a timescale appropriate to laboratory experiments. We provide evidence that both the dissolution of solid phases and exchange processes influence the εNd of leachates, which suggests that both processes may contribute to boundary exchange. We use major element and rare earth element (REE) data to investigate the pools of Nd that are accessed and demonstrate that sediment leachate εNd values cannot always be explained by admixture between an authigenic component and the bulk detrital component. For example, in core WIND 24B, acid-reductive leaching generates εNd values between −11 and −6 as a function of solution/solid ratios and leaching times, whereas the authigenic components have εNd ≈ −11 and the bulk detrital component has εNd ≈ −15. We infer that leaching in the Mascarene Basin accesses authigenic components and a minor radiogenic volcanic component that is more reactive than Madagascan-derived clays. The preferential mobilisation of such a minor component demonstrates that the Nd released by boundary exchange could often have a significantly different εNd composition than the bulk detrital sediment. These experiments further demonstrate certain limitations on the use of acid-reductive leaching to extract the εNd composition of the authigenic fraction of bulk deep sea sediments. For example, the detrital component may contain a reactive fraction which is also acid-extractible, while the incongruent nature of this dissolution suggests that it is often inappropriate to use the bulk detrital sediment elemental chemistry and/or εNd composition when assessing possible detrital contamination of leachates. Based on the highly systematic controls observed, and evidence from REE patterns on the phases extracted, we suggest two approaches that lead to the most reliable extraction of the authigenic εNd component and good agreement with foraminiferal-based approaches; either (i) leaching of sediments without a prior decarbonation step, or (ii) the use of short leaching times and low solution/solid ratios throughout

First Nd isotope record of Mediterranean–Atlantic water exchange through the Moroccan Rifian Corridor during the Messinian Salinity Crisis

We present the first neodymium isotope reconstruction of Mediterranean–Atlantic water exchange through the Moroccan (‘Rifian’) Corridor 8–5 Ma. This covers the late Miocene Messinian Salinity Crisis (MSC); a period when progressive tectonic restriction of the Mediterranean–Atlantic seaways resulted in extreme, basin-wide Mediterranean salinity fluctuations. The Rifian Corridor was one of these seaways and until now, relatively poor age constraints existed for the timing of Corridor closure, due to the impact of uplift and erosion on the sedimentary record. The bottom water Nd isotope record from the continuous Bou Regreg Valley succession in northwest Morocco allows us to explore corridor connectivity with the Atlantic. Data from the interior and Mediterranean edge of the Rifian Corridor (respectively, the Taza–Guercif and Melilla basins, northern Morocco) provide new information on corridor shallowing and the provenance of water flowing through the seaway. As a result, we can constrain the age of Rifian Corridor closure to 6.64–6.44 Ma. We also find no evidence of the siphoning of Atlantic waters through the seaway (7.20–6.58 Ma). Our results cannot exclude the possibility that at times during the Messinian Salinity Crisis, Mediterranean Outflow Water reached the Atlantic

Continental bedrock and riverine fluxes of strontium and neodymium isotopes to the oceans

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 11 (2010): Q03016, doi:10.1029/2009GC002869.Realistic models of past climate and ocean chemistry depend on reconstructions of the Earth's surface environments in the geologic past. Among the critical parameters is the geologic makeup of continental drainage. Here we show, for the present, that the isotope composition of dissolved strontium in rivers increases linearly with the age of bedrock in drainage basins, with the notable exception of the drainage area of Arabia, India, and Southeast Asia that is affected by unusually radiogenic dissolved Sr from the Himalaya. We also demonstrate that the neodymium isotope compositions of suspended matter in rivers as well as clastic sediments deposited along the ocean margins decrease linearly with the bedrock ages of river drainage basins and large-scale continental drainage regions, as determined from digital geologic maps. These correlations are used to calculate the present-day input of dissolved Sr (4.7 × 1010 mol yr−1, 87Sr/86Sr of ∼0.7111) and particulate Nd isotopes (ɛNd of approximately −7.3 ± 2.2) to the oceans. The fact that the regionally averaged ɛNd of the global detrital input to the global coastal ocean is identical to globally averaged seawater (ɛNd of −7.2 ± 0.5) lends credence to the importance of “boundary exchange” for the Nd isotope composition of water masses. Regional biases in source areas of detrital matter and runoff are reflected by the observation that the average age of global bedrock, weighted according to the riverine suspended sediment flux, is significantly younger (∼336 Myr) than the age of global bedrock weighted according to water discharge (394 Myr), which is younger than the average bedrock age of the nonglaciated, exorheic portions of the continents (453 Myr). The observation that the bedrock age weighted according to Sr flux is younger (339 Myr) than that weighted according to water flux reflects the disproportionate contribution from young sedimentary and volcanic rocks to the dissolved Sr load. Neither the isotope composition of the dissolved nor the particulate continental inputs to the ocean provide unbiased perspectives of the lithologic makeup of the Earth's surface. Temporal changes in bedrock geology as well as the shifting focal points of physical erosion and water discharge will undoubtedly have exerted strong controls on temporal and spatial changes in the isotope chemistry of past global runoff and thus seawater.NSF grants EAR‐ 0125873, EAR‐0519387, and OCE‐0851015 to B.P.‐E. and a CNRS‐funded “poste rouge” position for B.P.‐E. at the Observatoire Midi‐Pyrénées in Toulouse supported this work

Impact of glacial activity on the weathering of Hf isotopes – Observations from Southwest Greenland

Data for the modern oceans and their authigenic precipitates suggest incongruent release of hafnium (Hf) isotopes by chemical weathering of the continents. The fact that weathering during recent glacial periods is associated with more congruent release of Hf isotopes has led to the hypothesis that the incongruency may be controlled by retention of unradiogenic Hf by zircons, and that glacial grinding enhances release of Hf from zircons. Here we study the relationship between glacial weathering processes and Hf isotope compositions released to rivers fed by land-terminating glaciers of the Greenland Ice Sheet, as well as neighbouring non-glacial streams. The weathered source rocks in the studied area mostly consist of gneisses, but also include amphibolites of the same age (1.9 Ga). Hafnium and neodymium isotope compositions in catchment sediments and in the riverine suspended load are consistent with a predominantly gneissic source containing variable trace amounts of zircon and different abundances of hornblende, garnet and titanite. Glacially sourced rivers and non-glacial streams fed by precipitation and lakes show very unradiogenic Nd isotopic compositions, in a narrow range (ɛNd = −42.8 to −37.9). Hafnium isotopes, on the other hand, are much more radiogenic and variable, with ɛHf between −18.3 and −0.9 in glacial rivers, and even more radiogenic values of +15.8 to +46.3 in non-glacial streams. Although relatively unradiogenic Hf is released by glacial weathering, glacial rivers actually fall close to the seawater array in Hf-Nd isotope space and are not distinctly unradiogenic. Based on their abundance in rocks and sediments and their isotope compositions, different minerals contribute to the radiogenic Hf in solution with a decreasing relevance from garnet to titanite, hornblende and apatite. Neodymium isotopes preclude a much stronger representation of titanite, hornblende and apatite in solution, such as might result from differences in dissolution rates, than estimated from mineral abundance. The strong contrast in Hf isotope compositions between glacial rivers and non-glacial streams results mostly from different contributions from garnet and zircon, where zircon weathering is more efficient in the subglacial environment. A key difference between glacial and non-glacial waters is the water-rock interaction time. While glacial rivers receive continuous contributions from long residence time waters of distributed subglacial drainage systems, non-glacial streams are characterized by fast superficial drainage above the permafrost horizon. Therefore, the increased congruency in Hf isotope weathering in glacial systems could simply reflect the hydrological conditions at the base of the ice-sheet and glaciers, with zircon weathering contributions increasing with water-rock interaction time

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Parent proxy-report of their children's health-related quality of life: an analysis of 13,878 parents' reliability and validity across age subgroups using the PedsQL™ 4.0 Generic Core Scales

BACKGROUND: Health-related quality of life (HRQOL) measurement has emerged as an important health outcome in clinical trials, clinical practice improvement strategies, and healthcare services research and evaluation. While pediatric patient self-report should be considered the standard for measuring perceived HRQOL, there are circumstances when children are too young, too cognitively impaired, too ill or fatigued to complete a HRQOL instrument, and reliable and valid parent proxy-report instruments are needed in such cases. Further, it is typically parents' perceptions of their children's HRQOL that influences healthcare utilization. Data from the PedsQL™ Database(SM )were utilized to test the reliability and validity of parent proxy-report at the individual age subgroup level for ages 2–16 years as recommended by recent FDA guidelines. METHODS: The sample analyzed represents parent proxy-report age data on 13,878 children ages 2 to 16 years from the PedsQL™ 4.0 Generic Core Scales Database(SM). Parents were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which their children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 3,718, 26.8%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 10,160, 73.2%). RESULTS: The percentage of missing item responses for the parent proxy-report sample as a whole was 2.1%, supporting feasibility. The majority of the parent proxy-report scales across the age subgroups exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL™ scale and summary score, across age subgroups, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate the feasibility, reliability, and validity of parent proxy-report at the individual age subgroup for ages 2–16 years. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which reliable and valid responses across age categories are achievable. Even as pediatric patient self-report is advocated, there remains a fundamental role for parent proxy-report in pediatric clinical trials and health services research

Finding a Disappearing Nontimber Forest Resource: Using Grounded Visualization to Explore Urbanization Impacts on Sweetgrass Basketmaking in Greater Mt. Pleasant, South Carolina

Despite growing interest in urbanization and its social and ecological impacts on formerly rural areas, empirical research remains limited. Extant studies largely focus either on issues of social exclusion and enclosure or ecological change. This article uses the case of sweetgrass basketmaking in Mt. Pleasant, South Carolina, to explore the implications of urbanization, including gentrification, for the distribution and accessibility of sweetgrass, an economically important nontimber forest product (NTFP) for historically African American communities, in this rapidly growing area. We explore the usefulness of grounded visualization for research efforts that are examining the existence of fringe ecologies associated with NTFP. Our findings highlight the importance of integrated qualitative and quantitative analyses for revealing the complex social and ecological changes that accompany both urbanization and rural gentrification

Sculptors, architects, and painters conceive of depicted spaces differently

Sculptors, architects, and painters are three professional groups that require a comprehensive understanding of how to manipulate spatial structures. While it has been speculated that they may differ in the way they conceive of space due to the different professional demands, this has not been empirically tested. To achieve this, we asked architects, painters, sculptors, and a control group questions about spatially complex pictures. Verbalizations elicited were examined using cognitive discourse analysis. We found significant differences between each group. Only painters shifted consistently between 2D and 3D concepts, architects were concerned with paths and spatial physical boundedness, and sculptors produced responses that fell between architects and painters. All three differed from controls, whose verbalizations were generally less elaborate and detailed. Thus, for the case of sculptors, architects, and painters, profession appears to relate to a different spatial conceptualization manifested through a systematically contrasting way of talking about space