Generating a high-resolution global magnetic model for oil and mineral exploration

This is the final contribution to the trilogy of articles on global potential-field data compilations. Getech's continental and national magnetic data compilations commenced in 1989 and were designed specifically for use in petroleum and mineral exploration. These studies complemented the continental-scale gravity-compilation studies that were the subject of the TLE “Meter Reader” contributions in March and May of this year. The success of these projects resulted from strategic partnerships, especially with Paterson, Grant and Watson Ltd. (PGW), and links to a wide range of national organizations. Early compilations covering the whole of Africa, South America, and China were followed by large-scale, small-scale, and national compilations and continue to this day with compilations of U. S. surveys. The projects spawned a range of technical developments, including approaches to remove survey-line noise, the integration of survey grids and disparate ship-track data, and the preservation of the longest-wavelength anomalies associated with the crustal magnetic field. The resulting global gravity and magnetic grids now form an invaluable resource for resource exploration

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

The controls of radioelement distribution in the Etive and Cairngorm granites: Implications for heat production

Radiometric, whole rock trace element and petrological studies are reported for two late Caledonian granite complexes from the Grampian Highlands, Scotland. These studies throw light on the magmatic history of the intrusions and. more particularly. on their radioelement geochemistry and heat production which is interpreted in a geothermal context. The Etive Complex is a multiphase intrusion, ranging from diorite to granite in composition, emplaced by a cauldron subsidence mechanism. Its complex magmatic history involved crystal fractionation, both in-situ and at depth, coupled with episodic magma mixing in a deep magma chamber. Radioelement contents (means for the whole complex; 12.7 ppm Th, 2.9 ppm U, 4.1% K20) increase with magmatic differentiation and are concentrically zoned in the N Cruachan and Starav units. Mass balance calculations, incorporating radiometric, whole rock trace element, fission track and accessory phase microprobe data, show that uranium and thorium contents were, initially, controlled by the crystallisation of apatite + zircon + sphene ± allanite and chevkinite. Later, thorite and monazite became important thorium-hosts. Locally, enhanced uranium levels in the Starav Granites followed expulsion and limited outward migration of uranium-rich residual fluids. The distribution of radioelements in surface samples suggests that heat production decreases with depth in some units. Similar studies have identified four units in the Cairngorm Granite; NE Granite - Porphyritic Granite - Microgranite - Main Granite. Radioelement contents increase with magmatic evolution from the N Granite to the Main Granite; 26.5 > 32.3 ppm Th, 4.3 > 10.1 ppm U, 4.6 > 4.7% K20 (mean values). Uranium and thorium contents were controlled, predominantly, by the crystallisation of apatite + zircon + sphene ± allanite in the NE Granite and of apatite + zircon + monazite + xenotime + Nb-Ta-oxides ± thorite ± uraninite in the Main Granite. Minor amounts of uranium reside in secondary sites in hydrothermally altered samples. Modelled surface heat flow anomalies are 5.8 mW m-2 and 23.0 mW m-2 for the Etive Complex and Cairngorm Granite respectively. Comparison of calculated and preliminary heat flow measurements in the Cairngorm granite indicates that at least 35% of the observed heat flow arises from radioactive sources in the granite and that background heat flow is low

Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury

Many hundreds of thousands of people around the world are living with the long-term consequences of spinal cord injury and they need effective new therapies. Laboratory research in experimental animals has identified a large number of potentially translatable interventions but transition to the clinic is not straightforward. Further evidence of efficacy in more clinically-relevant lesions is required to gain sufficient confidence to commence human clinical trials. Of the many therapeutic candidates currently available, intraspinally applied chondroitinase ABC has particularly well documented efficacy in experimental animals. In this study we measured the effects of this intervention in a double-blinded randomized controlled trial in a cohort of dogs with naturally-occurring severe chronic spinal cord injuries that model the condition in humans. First, we collected baseline data on a series of outcomes: forelimb-hindlimb coordination (the prespecified primary outcome measure), skin sensitivity along the back, somatosensory evoked and transcranial magnetic motor evoked potentials and cystometry in 60 dogs with thoracolumbar lesions. Dogs were then randomized 1:1 to receive intraspinal injections of heat-stabilized, lipid microtube-embedded chondroitinase ABC or sham injections consisting of needle puncture of the skin. Outcome data were measured at 1, 3 and 6 months after intervention; skin sensitivity was also measured 24 h after injection (or sham). Forelimb-hindlimb coordination was affected by neither time nor chondroitinase treatment alone but there was a significant interaction between these variables such that coordination between forelimb and hindlimb stepping improved during the 6-month follow-up period in the chondroitinase-treated animals by a mean of 23%, but did not change in controls. Three dogs (10%) in the chondroitinase group also recovered the ability to ambulate without assistance. Sensitivity of the dorsal skin increased at 24 h after intervention in both groups but subsequently decreased to normal levels. Cystometry identified a non-significant improvement of bladder compliance at 1 month in the chondroitinase-injected dogs but this did not persist. There were no overall differences between groups in detection of sensory evoked potentials. Our results strongly support a beneficial effect of intraspinal injection of chondroitinase ABC on spinal cord function in this highly clinically-relevant model of chronic severe spinal cord injury. There was no evidence of long-term adverse effects associated with this intervention. We therefore conclude that this study provides strong evidence in support of initiation of clinical trials of chondroitinase ABC in humans with chronic spinal cord injury

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles.

α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson's disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65-97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65-97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS

Changing shape of disease: Nonalcoholic fatty liver disease in Crohnʼs disease—A case series and review of the literature:

With improvements in therapy for inflammatory bowel disease (IBD) and changes in the prevalence of obesity, the phenotype of Crohn's Disease (CD) is changing. These changes may herald an increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in this population

The mycobacterium lipid transporter MmpL3 is dimeric in detergent solution, SMALPs and reconstituted nanodiscs

The mycobacterial membrane protein large 3 (MmpL3) transports key precursor lipids to the outer membrane of Mycobacterium species. Multiple structures of MmpL3 from both M. tuberculosis and M. smegmatis in various conformational states indicate that the protein is both structurally and functionally monomeric. However, most other resistance, nodulation and cell division (RND) transporters structurally characterised to date are either dimeric or trimeric. Here we present an in depth biophysical and computational analysis revealing that MmpL3 from M. smegmatis exists as a dimer in a variety of membrane mimetic systems (SMALPs, detergent-based solution and nanodiscs). Sucrose gradient separation of MmpL3 populations from M. smegmatis, reconstituted into nanodiscs, identified monomeric and dimeric populations of the protein using laser induced liquid bead ion desorption (LILBID), a native mass spectrometry technique. Preliminary cryo-EM analysis confirmed that MmpL3 forms physiological dimers. Untargeted lipidomics experiments on membrane protein co-purified lipids revealed PE and PG lipid classes were predominant. Molecular dynamics (MD) simulations, in the presence of physiologically-relevant lipid compositions revealed the likely dimer interface

Antigenic and structural differences among six proteins II expressed by a single strain of Neisseria gonorrhoeae.

Gonococci express a family of related outer membrane proteins designated protein II (P.II), which undergo both phase and antigenic variation. Six P.II proteins have been identified in strain FA1090. We developed monoclonal antibodies specific for each P.II protein. Using these antibodies as probes, we purified the six different P.II proteins of this strain. Despite the relatedness of the proteins, we could not purify all of them by a single purification scheme. Four P.II proteins were purified by chromatofocusing, and the remaining two proteins were purified by hydrophobic interaction chromatography on phenyl-Sepharose. The N-terminal amino acid sequence of the proteins showed a high degree of sequence conservation. However, there was variability at specific amino acid residues, giving each P.II protein a unique N-terminal amino acid sequence. Thus P.II proteins of one strain differ among themselves not only in antigenic determinants and primary structure, but also in other characteristics affecting their properties in different chromatographic systems

Structure-Toxicity Relationship in Intermediate Fibrils from α-Synuclein Condensates

: The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson's disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity

Recent developments in genetics and medically assisted reproduction : from research to clinical applications

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.Peer reviewe