Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Paleozoic Stratigraphy and Structure at Iron Point, Humboldt County, North-Central Nevada

Detailed mapping and reconsideration of biostratigraphic data provide new insights into how the Comus Formation at its type locality at Iron Point, Humboldt County, Nevada fits into the regional stratigraphic framework. The age designation of the Comus Formation was reevaluated by this study using the most current understanding of Ordovician graptolite biostratigraphy. Previous studies at Iron Point had determined that the graptolites found in the siltstone units in the Comus Formation were middle Ordovician. This study determined that the species of graptolites found at Iron Point had been reclassified as late Ordovician since the original biostratigraphic study had been performed. A portion of the Vinini Formation at Iron Point was remapped in this study as the uppermost unit of the Comus Formation. Originally, this part of the Vinini Formation was mapped as a thrust “klippe” over the Comus Formation. This area originally mapped as “Vinini” is a very different rock type than the rest of the Vinini mapped at Iron Point. The lithology was much more similar to the underlying Comus Formation. Additionally, the geometry of the contact did not make sense; the thrust contact between the Vinini and the Comus was mapped as subhorizontal, however all of the strata dipped moderately to the west. The boundary between the "Vinini" and Comus Formation in this area was remapped and determined to be depositional, not structural. The Comus Formation in its type locality at Iron Point is not correlative with the "Comus Formation" that hosts Carlin-style gold deposits to the north in the Osgood Mountains. The Comus Formation at Iron Point is a sequence of interbedded carbonate and siliciclastic rocks deposited on the continental slope during the late Ordovician. The “Comus Formation” mapped in the Osgood Mountains is a sequence of carbonate, siliciclastic, and mafic volcanic rocks deposited on or near a carbonate seamount from the late Cambrian to late Ordovician (Hotz and Willden, 1964; Breit et al., 2005). The Comus at Iron Point and the “Comus” in the Osgood Mountains are composed of some similar types of Ordovician rocks, but their internal stratigraphy is too different to be classified as the same continuous unit. The Comus Formation at Iron Point is here interpreted to be correlative with the late Ordovician Hanson Creek Formation. These units have similar internal stratigraphy and timing of deposition. The Hanson Creek Formation was deposited on the continental shelf during the late Ordovician, and the Comus Formation is interpreted here to be the continuation of the Hanson Creek Formation onto the continental slope. A new unit composed of conglomerate, breccia, and a mature quartzite was identified at Iron Point underlying the Comus Formation. The quartzite portion of the unit was previously associated with the lower part of the Comus Formation, but the conglomerate and breccia were never recognized. The quartzite is composed entirely of quartz, and the conglomerate and breccia have a quartz sand matrix. The quartzite may be correlative with the middle Ordovician Eureka Quartzite. The Eureka Quartzite is the only widespread siliciclastic deposit on the continental shelf or slope during Paleozoic time. Additionally, the Eureka Quartzite underlies the Hanson Creek Formation and its correlative units in other areas in the Great Basin. Structural analyses using the new detailed mapping yielded evidence of six different deformational events at Iron Point. Their relative ages were determined through cross-cutting relationships and comparison to deformation recorded at Edna Mountain less than a kilometer east of Iron Point. The first fold set (F1) is west-vergent, and likely correlative to mid-Pennsylvanian folds observed at Edna Mountain (Villa, 2007; Cashman et al., 2011). F1 folds are asymmetric, steeply inclined, and locally overturned to the west. The second fold set (F2) records north-south contraction and is likely correlative to early Permian folds observed at Edna Mountain (Villa, 2007; Cashman et al., 2011). F2 folds are upright, symmetrical, and trend west-southwest. The King fault is a normal fault that strikes north-south and dips east. It post-dates the first two fold sets, and has not been active since the early Permian. The Silver Coin thrust strikes east-west, places the Vinini Formation over the Comus Formation, truncates the King fault, and is not affected by the first two fold sets. The West fault strikes southeast and dips southwest. The West fault truncates the Silver Coin thrust and juxtaposes the Comus and Vinini Formations in the footwall with the Cambrian Preble Formation in the hanging wall. Finally, Iron Point is bounded on the east side by the Pumpernickel fault, a normal fault that strikes north-south and dips east. The Pumpernickel fault Eureka Quartzite and Comus Formation in the footwall and the rock unit in the hanging wall is covered by Quaternary alluvium, so is not exposed. The movement on this structure is likely related to Basin and Range faulting starting in the Miocene

ESTIMATING POLYNYA CLOUDINESS

Global cloudiness distributions, though an important component in radiative and hydrological budgets, are neither adequately known nor easily retrieved by the spatial and spectral resolutions afforded by current satellite instrumentation. At high latitudes, cold, high albedo surfaces present a particular challenge to cloud retrieval, offering little or no thermal or visible contrast for cloud-ice discrimination. It is in these frequently cloudy and climate-sensitive regions that changing cloud amounts and optical parameters enact the greatest influence, enhancing or suppressing melt through cloud base emission of longwave radiation or scattering of incident shortwave radiation. Polynyas and leads, seasonally ice-free areas characterized by intense air-sea fluxes of heat and moisture, are useful features for exploring the relationships between cloud cover and the underlying surface. Using polar-optimized CASPR (Cloud and Surface Parameter Retrieval) algorithms to process multi-channel AVHRR radiances, cloud amounts, microphysics, and surface forcing are evaluated and validated against in situ measurements collected in several polynyas and leads across the Western Arctic during the years 1992-200

The fate of upwelled waters in the Great Whirl, August 1995

The Great Whirl is a large, anticyclonic gyre that develops off the northern Somali coast during the Southwest Monsoon. In August 1995 the NOAA Ship Malcolm Baldrige surveyed the seaward edge of the upwelling zone associated with this gyre. The fate of recently upwelled water was followed by mapping surface property distributions along a cool surface feature that extended seaward along the northern edge of the Great Whirl. Surface properties ( T, S, and chlorophyll a), surface velocity (ADCP), and XBT and CTD casts were interpreted in relation to the trajectories of three instrumented surface drifters deployed in the feature. Cool surface waters correspond in space to the shoaling of the upper thermocline and offshore advection from the coast. Surface chlorophyll a concentrations decreased from 2 to 3 μg l −1 in the upwelling zone to 0.5–1.5 μg l −1 in the surface feature and contiguous waters. Maximum surface velocities in the Great Whirl were 250 cm s −1 with velocities> 100 cm s −1 along the northern perimeter of the gyre. Decorrelation time-scales for u and v velocity components, and chlorophyll a fluorescence, from the drifters were on the order of 4 to 7 days. These times are comparable to those over which the drifters were ejected from the Great Whirl into the Socotra Gyre. Decorrelation times for sea-surface temperature were somewhat longer (10 days). All three platforms passed between the Somali coast and Socotra within a week of their deployment and then traveled east into the northern Arabian Sea

Implications of shortwave cloud forcing and feedbacks in the Southern Ocean

ABSTRACT. Measurements of the incident solar radiation taken during the Antarctic Remote Ic