Cascade Boltzmann - Langevin approach to higher-order current correlations in diffusive metal contacts

The Boltzmann - Langevin approach is extended to calculations of third and fourth cumulants of current in diffusive-metal contacts. These cumulants result from indirect correlations between current fluctuations, which may be considered as "noise of noise". The calculated third cumulant coincides exactly with its quantum-mechanical value. The fourth cumulant tends to its quantum-mechanical value $-e^3I/105$ at high voltages and to a positive value $2e^2T/3R$ at V=0 changing its sign at $eV \sim 20T$.Comment: 6 pages, 2 eps figures, typo corrected, minor change

Nickel and helium evidence for melt above the core–mantle boundary

High ^(3)He/^(4)He ratios in some basalts have generally been interpreted as originating in an incompletely degassed lower-mantle source. This helium source may have been isolated at the core–mantle boundary region since Earth’s accretion. Alternatively, it may have taken part in whole-mantle convection and crust production over the age of the Earth; if so, it is now either a primitive refugium at the core–mantle boundary or is distributed throughout the lower mantle. Here we constrain the problem using lavas from Baffin Island, West Greenland, the Ontong Java Plateau, Isla Gorgona and Fernandina (Galapagos). Olivine phenocryst compositions show that these lavas originated from a peridotite source that was about 20 per cent higher in nickel content than in the modern mid-ocean-ridge basalt source. Where data are available, these lavas also have high ^(3)He/^(4)He. We propose that a less-degassed nickel-rich source formed by core–mantle interaction during the crystallization of a melt-rich layer or basal magma ocean, and that this source continues to be sampled by mantle plumes. The spatial distribution of this source may be constrained by nickel partitioning experiments at the pressures of the core–mantle boundary

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin (PRX) gene. Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F

Enumeration of islets by nuclei counting and light microscopic analysis

Author Manuscript 2011 May 1.Islet enumeration in impure preparations by conventional dithizone staining and visual counting is inaccurate and operator dependent. We examined nuclei counting for measuring the total number of cells in islet preparations, and we combined it with morphological analysis by light microscopy (LM) for estimating the volume fraction of islets in impure preparations. Cells and islets were disrupted with lysis solution and shear, and accuracy of counting successively diluted nuclei suspensions was verified with (1) visual counting in a hemocytometer after staining with crystal violet, and automatic counting by (2) aperture electrical resistance measurement and (3) flow cytometer measurement after staining with 7-aminoactinomycin-D. DNA content averaged 6.5 and 6.9 pg of DNA per cell for rat and human islets, respectively, in agreement with literature estimates. With pure rat islet preparations, precision improved with increasing counts, and samples with about greater than or equal to 160 islets provided a coefficient of variation of about 6%. Aliquots of human islet preparations were processed for LM analysis by stereological point counting. Total nuclei counts and islet volume fraction from LM analysis were combined to obtain the number of islet equivalents (IEs). Total number of IE by the standard method of dithizone staining/manual counting was overestimated by about 90% compared with LM/nuclei counting for 12 freshly isolated human islet research preparations. Nuclei counting combined with islet volume fraction measurements from LM is a novel method for achieving accurate islet enumeration.National Institutes of Health (U.S.) (Grant NCRR ICR U4Z 16606)National Institutes of Health (U.S.) (Grant R01-DK063108-01A1)National Institutes of Health (U.S.) (Grant NCRR ICR U42 RR0023244-01)Joslin Diabetes and Endocrinology Research Center (Grant DK36836)Diabetes Research & Wellness FoundationJuvenile Diabetes Research Foundation International (Islet Transplantation, Harvard Medical School

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Cell Cycle Gene Networks Are Associated with Melanoma Prognosis

BACKGROUND: Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an in vitro functional genomics approach to understand melanoma molecular pathways. METHODOLOGY/PRINCIPAL FINDINGS: Affymetrix microarray data were generated from A375 melanoma cells treated in vitro with siRNAs against 45 transcription factors and signaling molecules. Analysis of this data using unsupervised hierarchical clustering and Bayesian gene networks identified proliferation-association RNA clusters, which were co-ordinately expressed across the A375 cells and also across melanomas from patients. The abundance in metastatic melanomas of these cellular proliferation clusters and their putative upstream regulators was significantly associated with patient prognosis. An 8-gene classifier derived from gene network hub genes correctly classified the prognosis of 23/26 metastatic melanoma patients in a cross-validation study. Unlike the RNA clusters associated with cellular proliferation described above, co-ordinately expressed RNA clusters associated with immune response were clearly identified across melanoma tumours from patients but not across the siRNA-treated A375 cells, in which immune responses are not active. Three uncharacterised genes, which the gene networks predicted to be upstream of apoptosis- or cellular proliferation-associated RNAs, were found to significantly alter apoptosis and cell number when over-expressed in vitro. CONCLUSIONS/SIGNIFICANCE: This analysis identified co-expression of RNAs that encode functionally-related proteins, in particular, proliferation-associated RNA clusters that are linked to melanoma patient prognosis. Our analysis suggests that A375 cells in vitro may be valid models in which to study the gene expression modules that underlie some melanoma biological processes (e.g., proliferation) but not others (e.g., immune response). The gene expression modules identified here, and the RNAs predicted by Bayesian network inference to be upstream of these modules, are potential prognostic biomarkers and drug targets

Exploring the Bimodal Solar System via Sample Return from the Main Asteroid Belt: The Case for Revisiting Ceres

Abstract: Sample return from a main-belt asteroid has not yet been attempted, but appears technologically feasible. While the cost implications are significant, the scientific case for such a mission appears overwhelming. As suggested by the “Grand Tack” model, the structure of the main belt was likely forged during the earliest stages of Solar System evolution in response to migration of the giant planets. Returning samples from the main belt has the potential to test such planet migration models and the related geochemical and isotopic concept of a bimodal Solar System. Isotopic studies demonstrate distinct compositional differences between samples believed to be derived from the outer Solar System (CC or carbonaceous chondrite group) and those that are thought to be derived from the inner Solar System (NC or non-carbonaceous group). These two groups are separated on relevant isotopic variation diagrams by a clear compositional gap. The interface between these two regions appears to be broadly coincident with the present location of the asteroid belt, which contains material derived from both groups. The Hayabusa mission to near-Earth asteroid (NEA) (25143) Itokawa has shown what can be learned from a sample-return mission to an asteroid, even with a very small amount of sample. One scenario for main-belt sample return involves a spacecraft launching a projectile that strikes an object and flying through the debris cloud, which would potentially allow multiple bodies to be sampled if a number of projectiles are used on different asteroids. Another scenario is the more traditional method of landing on an asteroid to obtain the sample. A significant range of main-belt asteroids are available as targets for a sample-return mission and such a mission would represent a first step in mineralogically and isotopically mapping the asteroid belt. We argue that a sample-return mission to the asteroid belt does not necessarily have to return material from both the NC and CC groups to viably test the bimodal Solar System paradigm, as material from the NC group is already abundantly available for study. Instead, there is overwhelming evidence that we have a very incomplete suite of CC-related samples. Based on our analysis, we advocate a dedicated sample-return mission to the dwarf planet (1) Ceres as the best means of further exploring inherent Solar System variation. Ceres is an ice-rich world that may be a displaced trans-Neptunian object. We almost certainly do not have any meteorites that closely resemble material that would be brought back from Ceres. The rich heritage of data acquired by the Dawn mission makes a sample-return mission from Ceres logistically feasible at a realistic cost. No other potential main-belt target is capable of providing as much insight into the early Solar System as Ceres. Such a mission should be given the highest priority by the international scientific community

The Iceland Microcontinent and a continental Greenland-Iceland-Faroe Ridge

The breakup of Laurasia to form the Northeast Atlantic Realm was the culmination of a long period of tectonic unrest extending back to the Late Palaeozoic. Breakup was prolonged and complex and disintegrated an inhomogeneous collage of cratons sutured by cross-cutting orogens. Volcanic rifted margins formed, which are blanketed by lavas and underlain variously by magma-inflated, extended continental crust and mafic high-velocity lower crust of ambiguous and probably partly continental provenance. New rifts formed by diachronous propagation along old zones of weakness. North of the Greenland-Iceland-Faroe Ridge the newly forming rift propagated south along the Caledonian suture. South of the Greenland-Iceland-Faroe Ridge it propagated north through the North Atlantic Craton along an axis displaced ~ 150 km to the west of the northern rift. Both propagators stalled where the confluence of the Nagssugtoqidian and Caledonian orogens formed a transverse barrier. Thereafter, the ~ 400-km-wide latitudinal zone between the stalled rift tips extended in a distributed, unstable manner along multiple axes of extension that frequently migrated or jumped laterally with shearing occurring between them in diffuse transfer zones. This style of deformation continues to the present day. It is the surface expression of underlying magma-assisted stretching of ductile mid- and lower continental crust which comprises the Icelandic-type lower crust that underlies the Greenland-Iceland-Faroe Ridge. This, and probably also one or more full-crustal-thickness microcontinents incorporated in the Ridge, are capped by surface lavas. The Greenland-Iceland-Faroe Ridge thus has a similar structure to some zones of seaward-dipping reflectors. The contemporaneous melt layer corresponds to the 3–10 km thick Icelandic-type upper crust plus magma emplaced in the ~ 10–30-km-thick Icelandic-type lower crust. This model can account for seismic and gravity data that are inconsistent with a gabbroic composition for Icelandic-type lower crust, and petrological data that show no reasonable temperature or source composition could generate the full ~ 40-km thickness of Icelandic-type crust observed. Numerical modeling confirms that extension of the continental crust can continue for many tens of Myr by lower-crustal flow from beneath the adjacent continents. Petrological estimates of the maximum potential temperature of the source of Icelandic lavas are up to 1450 °C, no more than ~ 100 °C hotter than MORB source. The geochemistry is compatible with a source comprising hydrous peridotite/pyroxenite with a component of continental mid- and lower crust. The fusible petrology, high source volatile contents, and frequent formation of new rifts can account for the true ~ 15–20 km melt thickness at the moderate temperatures observed. A continuous swathe of magma-inflated continental material beneath the 1200-km-wide Greenland-Iceland-Faroe Ridge implies that full continental breakup has not yet occurred at this latitude. Ongoing tectonic instability on the Ridge is manifest in long-term tectonic disequilibrium on the adjacent rifted margins and on the Reykjanes Ridge, where southerly migrating propagators that initiate at Iceland are associated with diachronous swathes of unusually thick oceanic crust. Magmatic volumes in the NE Atlantic Realm have likely been overestimated and the concept of a monogenetic North Atlantic Igneous Province needs to be reappraised. A model of complex, piecemeal breakup controlled by pre-existing structures that produces anomalous volcanism at barriers to rift propagation and distributes continental material in the growing oceans fits other oceanic regions including the Davis Strait and the South Atlantic and West Indian oceans