Landscape Genetics of Raccoons (\u3ci\u3eProcyon lotor\u3c/i\u3e) Associated with Ridges and Valleys of Pennsylvania: Implications for Oral Rabies Vaccination Programs

Raccoons are the reservoir for the raccoon rabies virus variant in the United States. To combat this threat, oral rabies vaccination (ORV) programs are conducted in many eastern states. To aid in these efforts, the genetic structure of raccoons (Procyon lotor) was assessed in southwestern Pennsylvania to determine if select geographic features (i.e., ridges and valleys) serve as corridors or hindrances to raccoon gene flow (e.g., movement) and, therefore, rabies virus trafficking in this physiographic region. Raccoon DNA samples (n = 185) were collected from one ridge site and two adjacent valleys in southwestern Pennsylvania (Westmoreland, Cambria, Fayette, and Somerset counties). Raccoon genetic structure within and among these study sites was characterized at nine microsatellite loci. Results indicated that there was little population subdivision among any sites sampled. Furthermore, analyses using a model-based clustering approach indicated one essentially panmictic population was present among all the raccoons sampled over a reasonably broad geographic area (e.g., sites up to 36 km apart). However, a signature of isolation by distance was detected, suggesting that widths of ORV zones are critical for success. Combined, these data indicate that geographic features within this landscape influence raccoon gene flow only to a limited extent, suggesting that ridges of this physiographic system will not provide substantial long-term natural barriers to rabies virus trafficking. These results may be of value for future ORV efforts in Pennsylvania and other eastern states with similar landscapes

Composite Materials for Hazard Mitigation of Reactive Metal Hydrides.

In an attempt to mitigate the hazards associated with storing large quantities of reactive metal hydrides, polymer composite materials were synthesized and tested under simulated usage and accident conditions. The composites were made by polymerizing vinyl monomers using free-radical polymerization chemistry, in the presence of the metal hydride. Composites with vinyl-containing siloxane oligomers were also polymerized with and without added styrene and divinyl benzene. Hydrogen capacity measurements revealed that addition of the polymer to the metal hydride reduced the inherent hydrogen storage capacity of the material. The composites were found to be initially effective at reducing the amount of heat released during oxidation. However, upon cycling the composites, the mitigating behavior was lost. While the polymer composites we investigated have mitigating potential and are physically robust, they undergo a chemical change upon cycling that makes them subsequently ineffective at mitigating heat release upon oxidation of the metal hydride. Acknowledgements The authors would like to thank the following people who participated in this project: Ned Stetson (U.S. Department of Energy) for sponsorship and support of the project. Ken Stewart (Sandia) for building the flow-through calorimeter and cycling test stations. Isidro Ruvalcaba, Jr. (Sandia) for qualitative experiments on the interaction of sodium alanate with water. Terry Johnson (Sandia) for sharing his expertise and knowledge of metal hydrides, and sodium alanate in particular. Marcina Moreno (Sandia) for programmatic assistance. John Khalil (United Technologies Research Corp) for insight into the hazards of reactive metal hydrides and real-world accident scenario experiments. Summary In an attempt to mitigate and/or manage hazards associated with storing bulk quantities of reactive metal hydrides, polymer composite materials (a mixture of a mitigating polymer and a metal hydride) were synthesized and tested under simulated usage and accident conditions. Mitigating the hazards associated with reactive metal hydrides during an accident while finding a way to keep the original capability of the active material intact during normal use has been the focus of this work. These composites were made by polymerizing vinyl monomers using free-radical polymerization chemistry, in the presence of the metal hydride, in this case a prepared sodium alanate (chosen as a representative reactive metal hydride). It was found that the polymerization of styrene and divinyl benzene could be initiated using AIBN in toluene at 70 degC. The resulting composite materials can be either hard or brittle solids depending on the cross-linking density. Thermal decomposition of these styrene-based composite materials is lower than neat polystyrene indicating that the chemical nature of the polymer is affected by the formation of the composite. The char-forming nature of cross-linked polystyrene is low and therefore, not an ideal polymer for hazard mitigation. To obtain composite materials containing a polymer with higher char-forming potential, siloxane-based monomers were investigated. Four vinyl-containing siloxane oligomers were polymerized with and without added styrene and divinyl benzene. Like the styrene materials, these composite materials exhibited thermal decomposition behavior significantly different than the neat polymers. Specifically, the thermal decomposition temperature was shifted approximately 100 degC lower than the neat polymer signifying a major chemical change to the polymer network. Thermal analysis of the cycled samples was performed on the siloxane-based composite materials. It was found that after 30 cycles the siloxane-containing polymer composite material has similar TGA/DSC-MS traces as the virgin composite material indicating that the polymer is physically intact upon cycling. Hydrogen capacity measurements revealed that addition of the polymer to the metal hydride in the form of a composite material reduced the inherent hydrogen storage capacity of the material. This reduction in capacity was observed to be independent of the amount of charge/discharge cycles except for the composites containing siloxane, which showed less of an impact on hydrogen storage capacity as it was cycled further. While the reason for this is not clear, it may be due to a chemically stabilizing effect of the siloxane on the metal hydride. Flow-through calorimetry was used to characterize the mitigating effectiveness of the different composites relative to the neat (no polymer) material. The composites were found to be initially effective at reducing the amount of heat released during oxidation, and the best performing material was the siloxane-containing composite which reduced the heat release to less than 50% of the value of the neat material. However, upon cycling the composites, all mitigating behavior was lost. The combined results of the flow-through calorimetry, hydrogen capacity, and thermogravimetric analysis tests lead to the proposed conclusion that while the polymer composites have mitigating potential and are physically robust under cycling, they undergo a chemical change upon cycling that makes them ineffective at mitigating heat release upon oxidation of the metal hydride

Interfacial behavior of polymer electrolytes

Evidence is presented concerning the effect of surfaces on the segmental motion of PEO-based polymer electrolytes in lithium batteries. For dry systems with no moisture the effect of surfaces of nano-particle fillers is to inhibit the segmental motion and to reduce the lithium ion transport. These effects also occur at the surfaces in composite electrodes that contain considerable quantities of carbon black nano-particles for electronic connection. The problem of reduced polymer mobility is compounded by the generation of salt concentration gradients within the composite electrode. Highly concentrated polymer electrolytes have reduced transport properties due to the increased ionic cross-linking. Combined with the interfacial interactions this leads to the generation of low mobility electrolyte layers within the electrode and to loss of capacity and power capability. It is shown that even with planar lithium metal electrodes the concentration gradients can significantly impact the interfacial impedance. The interfacial impedance of lithium/PEO-LiTFSI cells varies depending upon the time elapsed since current was turned off after polarization. The behavior is consistent with relaxation of the salt concentration gradients and indicates that a portion of the interfacial impedance usually attributed to the SEI layer is due to concentrated salt solutions next to the electrode surfaces that are very resistive. These resistive layers may undergo actual phase changes in a non-uniform manner and the possible role of the reduced mobility polymer layers in dendrite initiation and growth is also explored. It is concluded that PEO and ethylene oxide-based polymers are less than ideal with respect to this interfacial behavior

Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia

Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive days plus 14 or 7 days’ rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days’ rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-daily (BID) for 7 days plus 14 days’ rest in 21-day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-013-0050-9) contains supplementary material, which is available to authorized users

A portable neutron coincidence counter

Pacific Northwest National Laboratory has designed and constructed a prototype portable neutron coincidence counter intended for use in a variety of applications, such as the verification and inspection of weapons components, safety measurements for novel and challenging situations, portable portal deployment to prevent the transportation of fissile materials, uranium enrichment measurements in hard-to-reach locations, waste assays for objects that cannot be measured by existing measurement systems, and decontamination and decommissioning. The counting system weighs less than 40 kg and is composed of parts each weighing no more than 5 kg. In addition, the counter`s design is sufficiently flexible to allow rapid, reliable assembly around containers of nearly arbitrary size and shape. The counter is able to discern the presence of 1 kg of weapons-grade plutonium within an ALR-8 (30-gal drum) in roughly 100 seconds and 10 g in roughly 1000 seconds. The counter`s electronics are also designed for maximum adaptability, allowing operation under a wide variety of circumstances, including exposure to gamma-ray fields of 1 R/h. This report provides a detailed review of the design and construction process. Finally, preliminary experimental measurements that confirm the performance capabilities of this counter are discussed. 6 refs., 18 figs., 3 tabs

Locus-Specific Ribosomal RNA Gene Silencing in Nucleolar Dominance

The silencing of one parental set of rRNA genes in a genetic hybrid is an epigenetic phenomenon known as nucleolar dominance. We showed previously that silencing is restricted to the nucleolus organizer regions (NORs), the loci where rRNA genes are tandemly arrayed, and does not spread to or from neighboring protein-coding genes. One hypothesis is that nucleolar dominance is the net result of hundreds of silencing events acting one rRNA gene at a time. A prediction of this hypothesis is that rRNA gene silencing should occur independent of chromosomal location. An alternative hypothesis is that the regulatory unit in nucleolar dominance is the NOR, rather than each individual rRNA gene, in which case NOR localization may be essential for rRNA gene silencing. To test these alternative hypotheses, we examined the fates of rRNA transgenes integrated at ectopic locations. The transgenes were accurately transcribed in all independent transgenic Arabidopsis thaliana lines tested, indicating that NOR localization is not required for rRNA gene expression. Upon crossing the transgenic A. thaliana lines as ovule parents with A. lyrata to form F1 hybrids, a new system for the study of nucleolar dominance, the endogenous rRNA genes located within the A. thaliana NORs are silenced. However, rRNA transgenes escaped silencing in multiple independent hybrids. Collectively, our data suggest that rRNA gene activation can occur in a gene-autonomous fashion, independent of chromosomal location, whereas rRNA gene silencing in nucleolar dominance is locus-dependent

Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004).

BACKGROUND: The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance. METHODS: The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria. RESULTS: Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma. CONCLUSION: Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015

Postembryonic establishment of megabase-scale gene silencing in nucleolar dominance

Nucleolar dominance is an epigenetic phenomenon in plant and animal genetic hybrids that describes the expression of 45S ribosomal RNA genes (rRNA genes) inherited from only one progenitor due to the silencing of the other progenitor’s rRNA genes. rRNA genes are tandemly arrayed at nucleolus organizer regions (NORs) that span millions of basepairs, thus gene silencing in nucleolar dominance occurs on a scale second only to X-chromosome inactivation in female mammals. In Arabidopsis suecica, the allotetraploid hybrid of A. thaliana and A. arenosa, theA. thaliana –derived rRNA genes are subjected to nucleolar dominance and are silenced via repressive chromatin modifications. However, the developmental stage at which nucleolar dominance is established in A. suecica is currently unknown. We show that nucleolar dominance is not apparent in seedling cotyledons formed during embryogenesis but becomes progressively established during early postembryonic development in tissues derived from both the shoot and root apical meristems. The progressive silencing of A. thaliana rRNA genes correlates with the transition of A. thaliana NORs from a decondensed euchromatic state associated with histone H3 that is trimethylated on lysine 4 (H3K4me3) to a highly condensed heterochromatic state in which the NORs are associated with H3K9me2 and 5-methylcytosine-enriched chromocenters. In RNAi-lines in which the histone deacetylases HDA6 and HDT1 are knocked down, the developmentally regulated condensation and inactivation of A. thaliana NORs is disrupted. Collectively, these data demonstrate that HDA6 and HDT1 function in the postembryonic establishment of nucleolar dominance, a process which recurs in each generatio

Specific Receptor Usage in Plasmodium falciparum Cytoadherence Is Associated with Disease Outcome

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases

Development of a novel motivational interviewing (MI) informed peer-support intervention to support mothers to breastfeed for longer

Background: Many women in the UK stop breastfeeding before they would like to, and earlier than is recommended by the World Health Organization (WHO). Given the potential health benefits for mother and baby, new ways of supporting women to breastfeed for longer are required. The purpose of this study was to develop and characterise a novel Motivational Interviewing (MI) informed breastfeeding peer-support intervention. Methods: Qualitative interviews with health professionals and service providers (n=14), and focus groups with mothers (n=14), fathers (n=3), and breastfeeding peer-supporters (n=15) were carried out to understand experiences of breastfeeding peer-support and identify intervention options. Data were audio-recorded, transcribed, and analysed thematically. Consultation took place with a combined professional and lay Stakeholder Group (n=23). The Behaviour Change Wheel (BCW) guided intervention development process used the findings of the qualitative research and stakeholder consultation, alongside evidence from existing literature, to identify: the target behaviour to be changed; sources of this behaviour based on the Capability, Opportunity and Motivation (COM-B) model; intervention functions that could alter this behaviour; and; mode of delivery for the intervention. Behaviour change techniques included in the intervention were categorised using the Behaviour Change Technique Taxonomy Version 1 (BCTTv1). Results: Building knowledge, skills, confidence, and providing social support were perceived to be key functions of breastfeeding peer-support interventions that aim to decrease early discontinuation of breastfeeding. These features of breastfeeding peer-support mapped onto the BCW education, training, modelling and environmental restructuring intervention functions. Behaviour change techniques (BCTTv1) included social support, problem solving, and goal setting. The intervention included important inter-personal relational features (e.g. trust, honesty, kindness), and the BCTTv1 needed adaptation to incorporate this. Conclusions: The MI-informed breastfeeding peer-support intervention developed using this systematic and user-informed approach has a clear theoretical basis and well-described behaviour 3 change techniques. The process described could be useful in developing other complex interventions that incorporate peer-support and/or MI