Search

Much of the vertebrate skeleton develops from cartilage templates that are progressively remodeled into bone. Lineage tracing studies in mouse suggest that chondrocytes within these templates persist and become osteoblasts, yet the underlying mechanisms of this process and whether chondrocytes can generate other derivatives remain unclear. We find that zebrafish cartilages undergo extensive remodeling and vascularization during juvenile stages to generate fat-filled bones. Growth plate chondrocytes marked by sox10 and col2a1a contribute to osteoblasts, marrow adipocytes, and mesenchymal cells within adult bones. At the edge of the hypertrophic zone, chondrocytes re-enter the cell cycle and express leptin receptor (lepr), suggesting conversion into progenitors. Further, mutation of matrix metalloproteinase 9 (mmp9) results in delayed growth plate remodeling and fewer marrow adipocytes. Our data support Mmp9-dependent growth plate remodeling and conversion of chondrocytes into osteoblasts and marrow adipocytes as conserved features of bony vertebrates., eLife digest Our adult bones are made of a fatty tissue, called marrow, wrapped inside a hard outer layer produced by bone cells. They may appear stiff and unyielding, but our bones are actually dynamic structures. Early in life, most bones start as small ‘templates’ made of another, flexible tissue called cartilage. As the templates grow into adult bones, the cartilage is gradually replaced by bone and fat, but this process is still poorly understood. For example, it is not clear whether cartilage cells simply die and make way for new cells, or instead if they turn into bone and fat cells. To investigate this question, Giovannone, Paul et al. set out to follow the fate of early cartilage cells in zebrafish, and to compare this with what happens in mammals. Zebrafish were chosen because their skeleton and ours develop in similar ways; yet, these animals are much easier to study, in particular because their embryos are transparent. Young cartilage cells were ‘tagged’ with a long-lasting fluorescent protein in genetically engineered zebrafish embryos, and then followed over time. As the embryos started to form bones, the cartilage cells gave rise to bone cells, fat cells, and also potentially adult stem cells within the marrow, which can become other types of cells. This process required a protein called Mmp9, which also helps shape bone development in other organisms, including humans. Defects in how early cartilage templates morph into bone and fat may contribute to dwarfism and other severe conditions. Fully grasping the molecular mechanisms that preside over this complex transition may one day help design drugs to treat skeletal disorders.

Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting "peptope" comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4-mediated dissolution of a human AL amyloid extract implanted in mice.

Cranial sutures separate the skull bones and house stem cells for bone growth and repair. In Saethre-Chotzen syndrome, mutations in TCF12 or TWIST1 ablate a specific suture, the coronal. This suture forms at a neural-crest/mesoderm interface in mammals and a mesoderm/mesoderm interface in zebrafish. Despite this difference, we show that combinatorial loss of TCF12 and TWIST1 homologs in zebrafish also results in specific loss of the coronal suture. Sequential bone staining reveals an initial, directional acceleration of bone production in the mutant skull, with subsequent localized stalling of bone growth prefiguring coronal suture loss. Mouse genetics further reveal requirements for Twist1 and Tcf12 in both the frontal and parietal bones for suture patency, and to maintain putative progenitors in the coronal region. These findings reveal conservation of coronal suture formation despite evolutionary shifts in embryonic origins, and suggest that the coronal suture might be especially susceptible to imbalances in progenitor maintenance and osteoblast differentiation., eLife digest Some of the most common birth defects involve improper development of the head and face. One such birth defect is called craniosynostosis. Normally, an infant’s skull bones are not fully fused together. Instead, they are held together by soft tissue that allows the baby’s skull to more easily pass through the birth canal. This tissue also houses specialized cells called stem cells that allow the brain and skull to grow with the child. But in craniosynostosis these stem cells behave abnormally, which fuses the skull bones together and prevents the skull and brain from growing properly during childhood. One form of craniosynostosis called Saethre-Chotzen syndrome is caused by mutations in one of two genes that ensure the proper separation of two bones in the roof of the skull. Mice with mutations in the mouse versions of these genes develop the same problem and are used to study this condition. Mouse studies have looked mostly at what happens after birth. Studies looking at what happens in embryos with these mutations could help scientists learn more. One way to do so would be to genetically engineer zebrafish with the equivalent mutations. This is because zebrafish embryos are transparent and grow outside their mother’s body, making it easier for scientists to watch them develop. Now, Teng et al. have grown zebrafish with mutations in the zebrafish versions of the genes that cause Saethre-Chotzen syndrome. In the experiments, imaging tools were used to observe the live fish as they developed. This showed that the stem cells in their skulls become abnormal much earlier than previous studies had suggested. Teng et al. also showed that similar stem cells are responsible for growth of the skull in zebrafish and mice. Babies with craniosynostosis often need multiple, risky surgeries to separate their skull bones and allow their brain and head to grow. Unfortunately, these bones often fuse again because they have abnormal stem cells. Teng et al. provide new information on what goes wrong in these stem cells. Hopefully, this new information will help scientists to one day correct the defective stem cells in babies with craniosynostosis, thus reducing the number of surgeries needed to correct the problem.

Maternal intake of eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (22:6 n-3) has been associated with reduced adiposity in children, suggesting the possibility to program adipose development through dietary fatty acids before birth. This study determined if enriching the maternal diet in fish oil, the primary source of EPA and DHA, affected adipose development in offspring. Broiler chickens were used because they are obesity-prone, and because fatty acids provided to the embryo can be manipulated through the hen diet. Hens were fed diets supplemented (2.8% wt:wt) with corn oil (CO; n-6) or fish oil (FO; n-3) for 28 d. Chicks from both maternal diet groups were fed the same diet after hatch. Maternal FO consumption enriched chick adipose tissue in EPA and DHA and reduced adiposity by promoting more, but smaller, adipocytes. This adipocyte profile was paralleled by upregulated expression of the adipogenic regulator PPARG and its co-activator PPARGC1B, and reduced expression of LPL. Proteomics identified 95 differentially abundant proteins between FO and CO adipose tissue, including components of glucose metabolism, lipid droplet trafficking, and cytoskeletal organization. These results demonstrate that the maternal dietary fatty acid profile programs offspring adipose development.

This study offers insight into the roles anodic and cathodic processes play in electrochemically activated persulfate (EAP) and screens EAP as a viable technique for ciprofloxacin degradation in wastewater. Sulfate radical formation at a boron-doped diamond (BDD) anode and persulfate activation at a graphite cathode were experimentally elucidated using different electrolytes and electrochemical setups. Rapid ciprofloxacin transformation occurred via pseudo-first-order mechanisms with respect to ciprofloxacin in persulfate electrolyte, reaching 84% removal in 120 min using EAP. Transformation pathways were compared to those in nitrate and sulfate electrolytes. Ciprofloxacin removal rates in the electrochemical system were 88% and 33% faster in persulfate than nitrate and sulfate electrolytes, respectively. Total organic carbon removal rates were 93% and 48% faster in persulfate than nitrate and sulfate, respectively. Use of sulfate electrolyte resulted in removal rates 6-7 times faster than those in nitrate solution. Accelerated removal in sulfate was attributed to anodic sulfate radical formation, while enhanced removal in persulfate was associated with cathodic persulfate activation and nonradical persulfate activation at the BDD anode. Quenching experiments indicated both sulfate radicals and hydroxyl radicals contributed to degradation. Comparisons between platinum and graphite cathodes showed similar cathodic persulfate activation and ciprofloxacin degradation.

Ultra low-background radiation measurements are essential to several large-scale physics investigations. Assay of solid polymer materials for extremely low levels of radioactive elements, such as uranium, presents challenges. This paper describes an initial investigation into the use of laser ablation with inductively coupled plasma mass spectrometry for screening a solid plastic, polyethylene, for gross uranium levels.

Corrinoid auxotrophic organohalide-respiring Dehalococcoides mccartyi (Dhc) strains are keystone bacteria for reductive dechlorination of toxic and carcinogenic chloroorganic contaminants. We demonstrate that the lower base attached to the essential corrinoid cofactor of reductive dehalogenase (RDase) enzyme systems modulates dechlorination activity and affects the vinyl chloride (VC) RDases BvcA and VcrA differently. Amendment of 5,6-dimethylbenzimidazolyl-cobamide (DMB-Cba) to Dhc strain BAV1 and strain GT cultures supported cis-1,2-dichloroethene-to-ethene reductive dechlorination at rates of 107.0 (±12.0) μM and 67.4 (±1.4) μM Cl(-) released per day, respectively. Strain BAV1, expressing the BvcA RDase, reductively dechlorinated VC to ethene, although at up to fivefold lower rates in cultures amended with cobamides carrying 5-methylbenzimidazole (5-MeBza), 5-methoxybenzimidazole (5-OMeBza) or benzimidazole (Bza) as the lower base. In contrast, strain GT harboring the VcrA RDase failed to grow and dechlorinate VC to ethene in medium amended with 5-OMeBza-Cba or Bza-Cba. The amendment with DMB to inactive strain GT cultures restored the VC-to-ethene-dechlorinating phenotype and intracellular DMB-Cba was produced, demonstrating cobamide uptake and remodeling. The distinct responses of Dhc strains with BvcA versus VcrA RDases to different cobamides implicate that the lower base exerts control over Dhc reductive dechlorination rates and extents (that is, detoxification), and therefore the dynamics of Dhc strains with discrete reductive dechlorination capabilities. These findings emphasize that the role of the corrinoid/lower base synthesizing community must be understood to predict strain-specific Dhc activity and achieve efficacious contaminated site cleanup.

A new approach to isotopic purification has been developed and applied to the production of a small quantity of 244Pu with an isotopic purity >99.996 %, as compared against the standard 244Pu available that displays an isotopic purity of 97.87 %. The presence of Pu isotopes 239Pu, 240Pu, 241Pu and 242Pu have been greatly reduced, allowing for higher spiking levels of the isotopically purified 244Pu tracer to be used in environmental level sample analysis. Details of the isotopic purification process will be described along with the effect this improved Pu tracer could have on analytical Pu mass spectrometry measurements.

We provide a detailed, seismically defined three-dimensional model for the subducting plate interface along the Middle America Trench between Northern Nicaragua through to Southern Costa Rica. The model uses data from a weighted catalog of about 30,000 earthquake hypocenters compiled from nine catalogs to constrain the interface through a process we term the “Maximum Seismicity Method”. The method determines the average position of the largest cluster of microseismicity beneath an a priori functional surface above the interface. This technique is applied to all seismicity above 40 km depth, the approximate intersection of the hanging-wall Mohorovicic discontinuity, where seismicity likely lies along the plate interface. Below this depth, an envelope above 90% of seismicity approximates the slab surface. Because of station proximity to the interface, this model provides highest precision along the interface beneath the Nicoya Peninsula of Costa Rica, an area where marked geometric changes coincide with crustal transitions and topography observed seaward of the trench. The new interface is useful for a number of geophysical studies that aim to understand subduction zone earthquake behavior, geodynamic and tectonic development of convergent plate boundaries.

The prevalence of autism spectrum disorder (ASD) has seen a rapid increase in the past 20 years. Since autism was first introduced into the third edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Diagnostic and statistical manual (DSM-III). Washington, DC, 1980), the prevalence has risen to roughly 1 in every 68 children based on a recent study conducted by the Centers for Disease Control and Prevention (CDC, Morb Mortal Wkly Rep Surveill Summ 63(2):1–21, 2014). This rapid change in prevalence strongly contrasts the prior rates of 6 per every 1000 children in the 1990s (Wing and Potter, Dev Disabil Res Rev 8(3):151–161, 2002). Although multiple theories exist regarding the cause of this rise in prevalence, the most hypothesized reason is an increased awareness for it. More pediatricians are screening patients, more parents are aware of ASD symptoms, and it is even becoming more prominent in the media.

We report the development and testing of a collector arrangement for quadrupole inductively coupled plasma mass spectrometry (ICP-MS) that for the first time has been used to isolate small quantities of highly enriched (>99.99%) single isotopes, with deposition rates >10 ng h −1 . The collector assembly replaces the standard instrument detector allowing for implantation with simultaneous monitoring of the incident ion current. Even under zero bias implant conditions, low energy ( 151 Eu ion currents of 0.1–0.5 nA were collected on a simple, planar foil without resorting to any type of cup configuration. Recovery of the enriched isotope from such foils is much simpler than from a more complex cup configuration. High rejection of adjacent mass isotopes was demonstrated by selectively implanting 167 Er, then using laser ablation ICP-MS imaging to confirm the absence of any co-implanted 166 Er or 168 Er. The important analytical possibilities of this new approach to isotope ratio measurement, tracer purification, and radiation measurements are discussed.

Maternal intake of eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (22:6 n-3) has been associated with reduced adiposity in children, suggesting the possibility to program adipose development through dietary fatty acids before birth. This study determined if enriching the maternal diet in fish oil, the primary source of EPA and DHA, affected adipose development in offspring. Broiler chickens were used because they are obesity-prone, and because fatty acids provided to the embryo can be manipulated through the hen diet. Hens were fed diets supplemented (2.8% wt:wt) with corn oil (CO; n-6) or fish oil (FO; n-3) for 28 d. Chicks from both maternal diet groups were fed the same diet after hatch. Maternal FO consumption enriched chick adipose tissue in EPA and DHA and reduced adiposity by promoting more, but smaller, adipocytes. This adipocyte profile was paralleled by lower expression of the adipogenic regulator PPARG and its co-activator PPARGC1B, and elevated expression of LPL. Proteomics identified 95 differentially abundant proteins between FO and CO adipose tissue, including components of glucose metabolism, lipid droplet trafficking, and cytoskeletal organization. These results demonstrate that the maternal dietary fatty acid profile programs offspring adipose development.

The tear producing lacrimal gland is a tubular organ that protects and lubricates the ocular surface. While the lacrimal gland possesses many features that make it an excellent model to understand tubulogenesis, the cell types and lineage relationships that drive lacrimal gland formation are unclear. Using single cell sequencing and other molecular tools, we reveal novel cell identities and epithelial lineage dynamics that underlie lacrimal gland development. We show that the lacrimal gland from its earliest developmental stages is composed of multiple subpopulations of immune, epithelial, and mesenchymal cell lineages. The epithelial lineage exhibits the most substantiative cellular changes, transitioning through a series of unique transcriptional states to become terminally differentiated acinar, ductal and myoepithelial cells. Furthermore, lineage tracing in postnatal and adult glands provides the first direct evidence of unipotent KRT5+ epithelial cells in the lacrimal gland. Finally, we show conservation of developmental markers between the developing mouse and human lacrimal gland, supporting the use of mice to understand human development. Together, our data reveal critical features of lacrimal gland development that have broad implications for understanding epithelial organogenesis.

In this essay, the author reflects on the personal experience of the loss of his spouse, a reflection inspired and informed by the faith and theology of Karl Rahner. With death, it is not that a “new” time has begun, but that time itself has ended. And yet that mutual love as spouses continues. Life following the death of a spouse presents itself as an empty nothingness. But God, incomprehensible mystery, is our beginning. Our lives are filled with rupture and discontinuity not as evidence of a missing or absent God, but that we are not God.

Ultra-pure construction materials are required for the next generation of neutrino physics, dark matter and environmental science applications. These materials are also important for use in high-purity germanium spectrometers used in screening materials for radiopurity. The next-generation science applications require materials with radiopurity levels at or below 1 μBq/kg 232Th and 238U. Yet radiometric analysis lacks sensitivity below ~10 μBq/kg for the U and Th decay chains. This limits both the selection of clean materials and the validation of purification processes. Copper is an important high-purity material for low-background experiments due to the ease with which it can be purified by electrochemical methods. Electroplating for purification into near-final shapes, known as electroforming, is one such method. Continued refinement of the copper electroforming process is underway, for the first time guided by an ICP-MS based assay method that can measure 232Th and 238U near the desired purity levels. An assay of electroformed copper at a μBq/kg level has been achieved and is described. The implications of electroformed copper at or better than this purity on next-generation low-background experiments are discussed.

Aims The aim of this study was to isolate novel antibiofilm compounds produced by environmental bacteria. Methods and Results Cell-free extracts were prepared from lawns of bacteria cultured on agar. A total of 126 bacteria isolated from soil, cave and river habitats were employed. Extracts were tested for their ability to inhibit Staphylococcus aureus biofilm in a 96-well microtitre plate assay. A total of 55/126 extracts (44%) significantly inhibited Staph. aureus biofilm. Seven extracts were selected for further analysis. The antibiofilm activities in all seven extracts exhibited unique patterns of molecular mass, chemical polarity, heat stability and spectrum of activity against Staph. aureus, Staphylococcus epidermidis and Pseudomonas fluorescens, suggesting that these seven antibiofilm activities were mediated by unique chemical compounds with different mechanisms of action. Conclusions Environmental bacteria produce abundant and diverse antibiofilm compounds. Significance and Impact of the Study Screening cell-free extracts is a useful method for identifying secreted compounds that regulate biofilm formation. Such compounds may represent a novel source of antibiofilm agents for technological development.

Simple scoping models that can be used to evaluate ATF performance under severe accident conditions have been developed. The methodology provides a fundamental technical basis (a.k.a. metric) based on the thermodynamic boundary for evaluating performance relative to that of traditional Zr-based claddings. The initial focus in this study was on UO 2 fuel with the advanced claddings 310 SS, D9, FeCrAl, and SiC. The evaluation considered only energy release with concurrent combustible gas production from fuel–cladding–coolant interactions and, separately, molten core–concrete interactions at high temperatures. Other important phenomenological effects that can influence the rate and extent of cladding decomposition (e.g., eutectic interactions, degradation of other core constituents) were not addressed. For the cladding types addressed, potential combustible gas production under both in-vessel and ex-vessel conditions was similar to that for Zr. However, exothermic energy release from cladding oxidation was substantially less for iron-based alloys (by at least a factor of 4), and modestly less (by ∼20%) for SiC. Data on SiC-clad UO 2 fuel performance under severe accident conditions are sparse in the literature; thus, assumptions on the nature of the cladding decomposition process were made in order to perform this initial screening evaluation. Experimental data for this system under severe accident conditions is needed for a proper evaluation and comparison to iron-based claddings.

This work was supported by the National Institutes of Health NIH R01AL105690. Phosphatidylserine (PS) synthase (Cho1p) and the PS decarboxylase enzymes (Psd1p and Psd2p), which synthesize PS and phosphatidylethanolamine (PE), respectively, are crucial for Candida albicans virulence. Mutations that disrupt these enzymes compromise virulence. These enzymes are part of the cytidine diphosphate-diacylglycerol pathway (i.e. de novo pathway) for phospholipid synthesis. Understanding how losses of PS and/or PE synthesis pathways affect the phospholipidome of Candida is important for fully understanding how these enzymes impact virulence. The cho1Δ/Δ and psd1Δ/Δ psd2Δ/Δ mutations cause similar changes in levels of phosphatidic acid, phosphatidylglycerol, phosphatidylinositol and PS. However, only slight changes were seen in PE and phosphatidylcholine (PC). This finding suggests that the alternative mechanism for making PE and PC, the Kennedy pathway, can compensate for loss of the de novo synthesis pathway. Candida albicans Cho1p, the lipid biosynthetic enzyme with the most potential as a drug target, has been biochemically characterized, and analysis of its substrate specificity and kinetics reveal that these are similar to those previously published for Saccharomyces cerevisiae Cho1p. Postprint

In the ventral glial limitans (VGL) of the supraoptic nucleus (SON) of the rat, a unique astrocyte type is found with an ability to undergo striking morphological plasticity in response to a wide range of physiological stimulations such as chronic hypernatraemia. This includes a thinning of the VGL, which contains the somata and proximal processes of these astrocytes, as well as an almost complete withdrawal of their vertically-oriented distal processes. Currently, there is little information available on the types of astrocytes that reside in the SON-VGL and which of these exhibit state-dependent structural plasticity. To address this, we enabled the visualisation of single SON-VGL glia using two novel cell labelling techniques with fluorescence microscopy. First, we used an inducible genetic reporter mouse line that allowed the specific labelling of a low density of astrocytes expressing glutamate and aspartate transporter (GLAST)/excitatory amino acid transporter 1. This approach revealed a high degree of variability in the morphology of mouse SON-VGL astrocytes, in contrast to what has been reported for cortical astrocytes. Next, we used the DiOlistlic labelling approach to label single glial cells with DiI in the SON-VGL of rats. Astrocytes observed using this approach shared the morphological features of GLAST-expressing astrocytes in the mouse SON-VGL. Specific structural aspects of these cells were modified by chronic hypernatraemia achieved by 7-day salt loading. Notably, the average area of cells exhibiting protoplasmic features was significantly reduced in the horizontal plane, and the size of varicosities present on fibrous projections was significantly enlarged. These observations indicate that novel cell labelling methods can significantly advance our understanding of SON-VGL cells and reveal specific forms of morphological plasticity that can be driven by chronic hypernatraemia.

The coolability of ex-vessel core debris continues to be an issue of concern in the realm of light water reactor safety. Extensive research into corium/concrete interaction phenomena has been unable to establish the certainty of melt quench and stabilization within the containment boundary for all credible cases of cooling restricted to top flooding. As a result, there has been continuing interest in engineered systems that can augment cooling. This paper describes the testing of two passive cooling concepts that inject water into corium from below via nozzles embedded within the basemat: one with porous concrete nozzles and the other with a type of composite nozzle. The latter supplements water injection with noncondensable gas to stabilize flow and suppress vapor explosions. Each test involved a 136 kg melt composed of 56/23/14 wt% UO 2 /ZrO 2 /siliceous concrete at an initial depth of 30 cm. The setup with the porous concrete nozzles successfully injected water into the melt at heads as low as 2.3 m. The composite nozzle test was partially successful, with three nozzles delivering coolant while a fourth was damaged by the melt and failed to inject water. The melts cooled twice as fast as similar ones tested in a top flooding configuration. These experiments confirmed earlier work at Forschungszentrum Karlsruhe and elsewhere indicating that cooling via bottom water injection is a particularly effective method for quenching ex-vessel corium melts.

Astrocytes show a complex structural and physiological interplay with neurons and respond to neuronal activation in vitro and in vivo with intracellular calcium elevations. These calcium changes enable astrocytes to modulate synaptic transmission and plasticity through various mechanisms. However, the response pattern of astrocytes to single neuronal depolarization events still remains unresolved. This information is critical for fully understanding the coordinated network of neuron–glial signaling in the brain. To address this, we developed a system to map astrocyte calcium responses along apical dendrites of CA1 pyramidal neurons in hippocampal slices using single-neuron stimulation with channelrhodopsin-2. This technique allowed selective neuronal depolarization without invasive manipulations known to alter calcium levels in astrocytes. Light-evoked neuronal depolarization was elicited and calcium events in surrounding astrocytes were monitored using the calcium-sensitive dye Calcium Orange. Stimulation of single neurons caused calcium responses in populations of astrocytes along the apical axis of CA1 cell dendrites. Calcium responses included single events that were synchronized with neuronal stimulation and poststimulus changes in calcium event frequency, both of which were modulated by glutamatergic and purinergic signaling. Individual astrocytes near CA1 cells showed low ability to respond to repeated neuronal depolarization events. However, the response of the surrounding astrocyte population was remarkably accurate. Interestingly, the reliability of responses was graded with respect to astrocyte location along the CA1 cell dendrite, with astrocytes residing in the primary dendrite subregion being most responsive. This study provides a new perspective on the dynamic response property of astrocyte ensembles to neuronal activity.

Lanthanides are common fission products and the ability to separate and quantify these elements is critical to rapid radiochemistry applications. Published lanthanide separations using Eichrom Ln Spec resin utilize an HCl gradient. Here it is shown that the efficacy and resolution of the separation is improved when a nitric acid gradient is used instead. The described method allows parallel processing of many samples in 1.5 h followed by 60 min counting for quantification of 9 radioisotopes of 7 lanthanide elements.

The Mercury Laser Altimeter on the NASA MESSENGER mission has ranged to several ridges and lobate scarps during two equatorial flybys of the planet Mercury. The tectonic features sampled, like others documented by spacecraft imaging and Earth-based radar, are spatially isolated and have vertical relief in excess of 1 km. The profiles also indicate that the faulting associated with their formation penetrated to tens of kilometers depth into the lithosphere and accommodated substantial shortening. To gain insight into the mechanism(s) of strain accommodation across these structures, we perform analytical and numerical modeling of representative dynamic localization mechanisms. We find that ductile localization due to shear heating is not favored, given our current understanding of thermal gradients and shallow thermal structure of Mercury at the time of ridge and scarp formation, and is likely to be of secondary importance at best. Brittle localization, associated with loss of resistance during fault development or with velocity weakening during sliding on mature faults, is weakly localizing but permits slip to accumulate over geological time scales. The range of shallow thermal gradients that produce isolated faults rather than distributed fault sets under the assumption of modest fault weakening is consistent with previous models for Mercury’s early global thermal history. To be consistent with strain rates predicted from thermal history models and the amount of shortening required to account for the underlying large-offset faults, ridges and scarps on Mercury likely developed over geologically substantial time spans.

SUMMARY The 2008 June 8, moment magnitude MW 6.4 crustal earthquake in northwestern Peloponnese, Greece, was a strong-shaking dextral strike-slip event with teleseismic broad-band and high-frequency energy magnitudes Me of 6.8 and 7.2, respectively. A high stress drop 5–10 times the global average is associated with excessive high-frequency energy. The NE–SW trending fault plane shown by the aftershock distribution and focal mechanism is not associated with previously mapped faults, and no obvious coseismic surface rupture was discovered. Contrasting the enhanced rupture energy, the event created no substantial coseismic or post-seismic surface deformation, likely due to a fault buried below a detached thick and compositionally weak flysch layer. Comparative spatial analysis including over 30 regional strike-slip events between 1965 and 2009 reveals a NE–SW striking diffuse transform fault zone subparallel to the Cephalonia Transform Fault. The dextral sense of motion along the transform zone is consistent with the ongoing Global Positioning System (GPS)-derived deformation along the West Hellenic Arc and the motion on the Cephalonia Transform Fault. Characterizing this system is important to constraining the seismic hazard near Patras, a major port city immediately NE of the 2008 event.

Corium strength is of interest in the context of a severe reactor accident in which molten core material melts through the reactor vessel and collects on the containment basemat. Some accident management strategies involve pouring water over the melt to solidify it and halt corium/concrete interactions. The effectiveness of this method could be influenced by the strength of the corium crust at the interface between the melt and coolant. A strong, coherent crust anchored to the containment walls could allow the yet-molten corium to fall away from the crust as it erodes the basemat, thereby thermally decoupling the melt from the coolant and sharply reducing the cooling rate. This paper presents a diverse collection of measurements of the mechanical strength of corium. The data is based on load tests of corium samples in three different contexts: (1) small blocks cut from the debris of the large-scale MACE experiments, (2) 30 cm-diameter, 75 kg ingots produced by SSWICS quench tests, and (3) high temperature crusts loaded during large-scale corium/concrete interaction (CCI) tests. In every case the corium consisted of varying proportions of UO2, ZrO2, and the constituents of concrete to represent a LWR melt at different stages of a molten core/concrete interaction. The collection of data was used to assess the strength and stability of an anchored, plant-scale crust. The results indicate that such a crust is likely to be too weak to support itself above the melt. It is therefore improbable that an anchored crust configuration could persist and the melt become thermally decoupled from the water layer to restrict cooling and prolong an attack of the reactor cavity concrete.

Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.

In the wake of the Three Mile Island accident, vigorous research efforts were initiated to acquire a basic knowledge of the progression and consequences of accidents that involve a substantial degree of core degradation and melting. The primary emphasis of this research was placed on containment integrity, with: i) hydrogen combustion-detonation, ii) steam explosion, iii) direct containment heating (DCH), and iv) melt attack on the BWR Mark-I containment shell identified as energetic processes that could lead to early containment failure (i.e., within the first 24 hours of the accident). Should the core melt fail the reactor vessel, then non-condensable gas production from Molten Core-Concrete Interaction (MCCI) was identified as a mechanism that could fail the containment by pressurization over the long term. One signification question that arose as part of this investigation was the effectiveness of water in terminating an MCCI by flooding the interacting masses from above, thereby quenching the molten core debris and rendering it permanently coolable. Successful quenching of the core melt would prevent basemat melt through, as well as continued containment pressurization by non-condensable gas production, and so the accident progression would be successfully terminated without release of radioactivity to the environment. Based on these potential merits, ex-vessel corium coolability has been the focus of extensive research over the last 20 years as a potential accident management strategy for current plants. In addition, outcomes from this research have impacted the accident management strategies for the Gen III+ LWR plant designs that are currently being deployed around the world. This paper provides: i) an historical overview of corium coolability research, ii) summarizes the current status of research in this area, and iii) highlights trends in severe accident management strategies that have evolved based on the findings from this work.

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.

The goals of the Global Nuclear Energy Partnership (GNEP) are to expand the use of nuclear energy to meet increasing global energy demand in an environmentally sustainable manner, to address nuclear waste management issues without making separated plutonium, and to address nonproliferation concerns. The advanced burner reactor (ABR) is a fast reactor concept which supports the GNEP fuel cycle system. Since the integral fast reactor (IFR) and advanced liquid-metal reactor (ALMR) projects were terminated in 1994, there has been no major development on sodium-cooled fast reactors in the United States. Therefore, in support of the GNEP fast reactor program, the history of sodium-cooled reactor development was reviewed to support the initiation of this technology within the United States and to gain an understanding of the technology gaps that may still remain for sodium fast reactor technology. The fuel-handling system is a key element of any fast reactor design. The major functions of this system are to receive, test, store, and then load fresh fuel into the core; unload from the core; then clean, test, store, and ship spent fuel. Major requirements are that the system must be reliable and relatively easy to maintain. In addition, the system should be designed more » so that it does not adversely impact plant economics from the viewpoints of capital investment or plant operations. In this gap analysis, information on fuel-handling operating experiences in the following reactor plants was carefully reviewed: EBR-I, SRE, HNPF, Fermi, SEFOR, FFTF, CRBR, EBR-II, DFR, PFR, Rapsodie, Phenix, Superphenix, KNK, SNR-300, Joyo, and Monju. The results of this evaluation indicate that a standardized fuel-handling system for a commercial fast reactor is yet to be established. However, in the past sodium-cooled reactor plants, most major fuel-handling components-such as the rotatable plug, in-vessel fuel-handling machine, ex-vessel fuel transportation cask, ex-vessel sodium-cooled storage, and cleaning stations-have accumulated satisfactory construction and operation experiences. In addition, two special issues for future development are described in this report: large capacity interim storage and transuranic-bearing fuel handling. « less

During World War II, the Hanford Site in Washington became the location for U.S. plutonium production. In 2004, a bottle containing a sample of plutonium was recovered from a Hanford waste trench. Here, state-of-the-art instrumental analyses, reactor model simulations, and investigative science techniques were used to provide insights as to the origin of this unknown sample, a process collectively termed as nuclear archeology. Isotopic age dating conducted on the sample in 2007 indicated the sample was separated from the spent fuel 61.6 +/- 4.5 years earlier. The isotope (22)Na, a detectable product of a secondary nuclear reaction, proved useful as a powerful tool for nuclear forensic analysis as (1) an easily detectable signifier of the presence of alpha emitting actinides, (2) an indicator of sample splitting, and (3) a measure of the time since sample splitting. Analytical results of minor actinide isotopes and reactor model simulations confirmed the material originated from the X-10 reactor in Oak Ridge, TN. Corroborated by historical documents, we concluded this sample was part of the first batch of Pu separated at T-Plant, Hanford, the world's first industrial-scale reprocessing facility, on December 9, 1944. This sample represents the oldest known collection of man-made (239)Pu in the world.

CFE88 is a conserved essential gene product from Streptococcus pneumoniae. This 227-residue protein has minimal sequence similarity to proteins of known 3D structure. Sequence alignment models and computational protein threading studies suggest that CFE88 is a methyltransferase. Characterization of the conformation and function of CFE88 has been performed by using several techniques. Backbone atom and limited side-chain atom NMR resonance assignments have been obtained. The data indicate that CFE88 has two domains: an N-terminal domain with 163 residues and a C-terminal domain with 64 residues. The C-terminal domain is primarily helical, while the N-terminal domain has a mixed helical/extended (Rossmann) fold. By aligning the experimentally observed elements of secondary structure, an initial unrefined model of CFE88 has been constructed based on the X-ray structure of ErmC' methyltransferase (Protein Data Bank entry 1QAN). NMR and biophysical studies demonstrate binding of S-adenosyl-L-homocysteine (SAH) to CFE88; these interactions have been localized by NMR to the predicted active site in the N-terminal domain. Mutants that target this predicted active site (H26W, E46R, and E46W) have been constructed and characterized. Overall, our results both indicate that CFE88 is a methyltransferase and further suggest that the methyltransferase activity is essential for bacterial survival.

The goals of the Global Nuclear Energy Partnership (GNEP) are to expand the use of nuclear energy to meet increasing global energy demand in an environmentally sustainable manner, to address nuclea...

Spectrometers for the lowest-level radiometric measurements require materials of extreme radiopurity. Measurements of rare nuclear decays, e.g., neutrinoless double-beta decay, can require construction and shielding materials with bulk radiopurity reaching one micro-Becquerel per kilogram or less. When such extreme material purity is achieved, surface contamination, particularly solid daughters in the natural radon decay chains, can become the limiting background. High-purity copper is an important material for ultra-low-background spectrometers and thus is the focus of this work. A method for removing surface contamination at very low levels without attacking the bulk material is described. An assay method using a low-background proportional counter made of the material under examination is employed, and the preliminary result of achievable surface contamination levels is presented.