Isomer depletion as experimental evidence of nuclear excitation by electron capture.

The atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a γ-ray. This 'internal conversion' has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons. In the inverse process-nuclear excitation by electron capture (NEEC)-a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted in 1976 and has not hitherto been observed. Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments, in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of 'isomer depletion', which has been investigated previously through other reactions, but is used here to obtain evidence for NEEC.

The Angular Distribution of Lower Band Chorus Waves Near Plasmaspheric Plumes.

Plumes have been identified as an access region for chorus waves to enter the plasmasphere. Here, for the first time, chorus wave properties are parameterized by distance from the plume boundary. Case studies and statistical analysis indicate that the polar wave vector angle, θ k , of chorus becomes more oblique near the plume edge. Occurrence rates of θ k > 35° on the plume boundary are approximately double that observed further away from the plume. Whilst the increase in θ k is apparent on both plume edges, the distribution of θ k exhibits different behavior between the Eastward and Westward boundaries. In general, the distribution of azimuthal wave vector angles, ϕ k , is symmetric about the anti-Earthwards direction. However, near the Eastward plume boundary, an Eastwards skew of ϕ k is reported. This result provides new insight on chorus propagation in the context of the chorus-to-hiss mechanism, and has implications for quantifying wave-particle interactions in the near-plume region.

Longitudinal Wobbling Motion in

The rare phenomenon of nuclear wobbling motion has been investigated in the nucleus ^{187}Au. A longitudinal wobbling-bands pair has been identified and clearly distinguished from the associated signature-partner band on the basis of angular distribution measurements. Theoretical calculations in the framework of the particle rotor model are found to agree well with the experimental observations. This is the first experimental evidence for longitudinal wobbling bands where the expected signature partner band has also been identified, and establishes this exotic collective mode as a general phenomenon over the nuclear chart.

Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Evidence for Rigid Triaxial Deformation in

An extensive, model-independent analysis of the nature of triaxial deformation in ^{76}Ge, a candidate for neutrinoless double-beta (0νßß) decay, was carried out following multistep Coulomb excitation. Shape parameters deduced on the basis of a rotational-invariant sum-rule analysis provided considerable insight into the underlying collectivity of the ground-state and γ bands. Both sequences were determined to be characterized by the same ß and γ deformation parameter values. In addition, compelling evidence for low-spin, rigid triaxial deformation in ^{76}Ge was obtained for the first time from the analysis of the statistical fluctuations of the quadrupole asymmetry deduced from the measured E2 matrix elements. These newly determined shape parameters are important input and constraints for calculations aimed at providing, with suitable accuracy, the nuclear matrix elements relevant to 0νßß.

Selective RET kinase inhibition for patients with RET-altered cancers.

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Masses and ß-Decay Spectroscopy of Neutron-Rich Odd-Odd

The structure of deformed neutron-rich nuclei in the rare-earth region is of significant interest for both the astrophysics and nuclear structure fields. At present, a complete explanation for the observed peak in the elemental abundances at A∼160 eludes astrophysicists, and models depend on accurate quantities, such as masses, lifetimes, and branching ratios of deformed neutron-rich nuclei in this region. Unusual nuclear structure effects are also observed, such as the unexpectedly low energies of the first 2^{+} levels in some even-even nuclei at N=98. In order to address these issues, mass and ß-decay spectroscopy measurements of the ^{160}Eu_{97} and ^{162}Eu_{99} nuclei were performed at the Californium Rare Isotope Breeder Upgrade radioactive beam facility at Argonne National Laboratory. Evidence for a gap in the single-particle neutron energies at N=98 and for large deformation (ß_{2}∼0.3) is discussed in relation to the unusual phenomena observed at this neutron number.

Transverse wobbling in

A pair of transverse wobbling bands is observed in the nucleus ^{135}Pr. The wobbling is characterized by ΔI=1, E2 transitions between the bands, and a decrease in the wobbling energy confirms its transverse nature. Additionally, a transition from transverse wobbling to a three-quasiparticle band comprised of strong magnetic dipole transitions is observed. These observations conform well to results from calculations with the tilted axis cranking model and the quasiparticle rotor model.

Decay and Fission Hindrance of Two- and Four-Quasiparticle K Isomers in

Two isomers decaying by electromagnetic transitions with half-lives of 4.7(1.1) and 247(73) µs have been discovered in the heavy ^{254}Rf nucleus. The observation of the shorter-lived isomer was made possible by a novel application of a digital data acquisition system. The isomers were interpreted as the K^{π}=8^{-}, ν^{2}(7/2^{+}[624],9/2^{-}[734]) two-quasineutron and the K^{π}=16^{+}, 8^{-}ν^{2}(7/2^{+}[624],9/2^{-}[734])⊗8^{-}π^{2}(7/2^{-}[514],9/2^{+}[624]) four-quasiparticle configurations, respectively. Surprisingly, the lifetime of the two-quasiparticle isomer is more than 4 orders of magnitude shorter than what has been observed for analogous isomers in the lighter N=150 isotones. The four-quasiparticle isomer is longer lived than the ^{254}Rf ground state that decays exclusively by spontaneous fission with a half-life of 23.2(1.1) µs. The absence of sizable fission branches from either of the isomers implies unprecedented fission hindrance relative to the ground state.

The Electric and Magnetic Fields Instrument Suite and Integrated Science (EMFISIS): Science, Data, and Usage Best Practices.

We provide a post-mission assessment of the science and data from the Electric and Magnetic Field Instrument Suite and Integrated Science (EMFISIS) investigation on the NASA Van Allen Probes mission. An overview of important scientific results is presented, covering all of the key wave modes and DC magnetic fields measured by EMFISIS. Discussion of the data products, which are publicly available, follows to provide users with guidance on characteristics and known issues of the measurements. We present guidance on the correct use of derived products, in particular, the wave-normal analysis (WNA) which yields fundamental wave properties such as polarization, ellipticity, and Poynting flux. We also give information about the plasma density derived from measuring the upper hybrid line in the inner magnetosphere.

Event-based biosurveillance of respiratory disease in Mexico, 2007-2009: connection to the 2009 influenza A(H1N1) pandemic?

The emergence of the 2009 pandemic influenza A(H1N1) virus in North America and its subsequent global spread highlights the public health need for early warning of infectious disease outbreaks. Event-based biosurveillance, based on local- and regional-level Internet media reports, is one approach to early warning as well as to situational awareness. This study analyses media reports in Mexico collected by the Argus biosurveillance system between 1 October 2007 and 31 May 2009. Results from Mexico are compared with the United States and Canadian media reports obtained from the HealthMap system. A significant increase in reporting frequency of respiratory disease in Mexico during the 2008-9 influenza season relative to that of 2007-8 was observed (p<0.0001). The timing of events, based on media reports, suggests that respiratory disease was prevalent in parts of Mexico, and was reported as unusual, much earlier than the microbiological identification of the pandemic virus. Such observations suggest that abnormal respiratory disease frequency and severity was occurring in Mexico throughout the winter of 2008-2009, though its connection to the emergence of the 2009 pandemic influenza A(H1N1) virus remains unclear.

Use of a novel drape 'tent' as an infection prevention control measure for mastoid surgery.

BACKGROUND: Mastoid surgery is an aerosol-generating procedure that involves the use of a high-speed drill, which produces a mixture of water, bone, blood and tissue that may contain the viable coronavirus disease 2019 pathogen. This potentially puts the surgeon and other operating theatre personnel at risk of acquiring the severe acute respiratory syndrome coronavirus-2 from contact with droplets or aerosols. The use of an additional drape designed to limit the spread of droplets and aerosols has been described; such drapes include the 'Southampton Tent' and 'OtoTent'. OBJECTIVES: To evaluate the use of a novel drape 'tent' that has advantages over established 'tent' designs in terms of having: (1) a CE marking; (2) no requirement for modification during assembly; and (3) no obstruction to the surgical visual field. RESULTS AND CONCLUSION: During mastoid surgery, the dispersion of macroscopic droplets and other particulate matter was confined within the novel drape 'tent'. Use of this drape 'tent' had no adverse effects upon the surgeon's manual dexterity or efficiency, the view of the surgical field, or the sterility. Hence, our findings support its use during mastoid surgery in the coronavirus disease 2019 era.

Potential sites of PI-3 kinase function in the endocytic pathway revealed by the PI-3 kinase inhibitor, wortmannin.

Previously we have shown that PDGF receptor mutants that do not bind PI-3 kinase internalize after ligand binding, but fail to downregulate and degrade. To define further the role of PI-3 kinase in trafficking processes in mammalian cells, we have investigated the effects of a potent inhibitor of PI-3 kinase activity, wortmannin. At nanomolar concentrations, wortmannin inhibited both the transfer of PDGF receptors from peripheral compartments to juxtanuclear vesicles, and their subsequent degradation. In contrast, the delivery of soluble phase markers to lysosomes, assessed by the accumulation of Lucifer yellow (LY) in perinuclear vesicles after 120 min of incubation, was not blocked by wortmannin. Furthermore, wortmannin did not affect the rate of transferrin uptake, and caused only a small decrease in its rate of recycling. Thus, the effects of wortmannin on PDGFr trafficking are much more pronounced than its effects on other endocytic events. Unexpectedly, wortmannin also caused a striking effect on the morphology of endosomal compartments, marked by tubulation and enlargement of endosomes containing transferrin or LY. This effect was somewhat similar to that produced by brefeldin A, and was also blocked by pre-treatment of cells with aluminum fluoride (AlF4-). These results suggest two sites in the endocytic pathway where PI-3 kinase activity may be required: (a) to sort PDGF receptors from peripheral compartments to the lysosomal degradative pathway; and (b) to regulate the structure of endosomes containing lysosomally directed and recycling molecules. This latter function could be mediated through the activation of AlFt4-)-sensitive GTP-binding proteins downstream of PI-3 kinase.

The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity.

High concentrations of potent N-methyl-D-aspartate (NMDA) agonists can trigger degeneration of cultured mouse cortical neurons after an exposure of only a few minutes; in contrast, selective non-NMDA agonists or low levels of NMDA agonists require exposures of several hours to induce comparable damage. The dihydropyridine calcium channel antagonist nifedipine was used to test whether this slow neurotoxicity is mediated by a calcium influx through voltage-gated channels. Nifedipine had little effect on the widespread neuronal degeneration induced by brief exposure to high concentrations of NMDA but substantially attenuated the neurotoxicity produced by 24-hour exposure to submaximal concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or quinolinate. Calcium ion influx through dihydropyridine-sensitive, voltage-dependent calcium channels may be an important step in the neuronal injury induced by the prolonged activation of NMDA or non-NMDA glutamate receptors.

Atmospheric Trends and Lifetime of CH3CCI3 and Global OH Concentrations.

Determination of the atmospheric concentrations and lifetime of trichloroethane (CH(3)CCI(3)) is very important in the context of global change. This halocarbon is involved in depletion of ozone, and the hydroxyl radical (OH) concentrations determined from its lifetime provide estimates of the lifetimes of most other hydrogen-containing gases involved in the ozone layer and climate. Global measurements of trichloroethane indicate rising concentrations before and declining concentrations after late 1991. The lifetime of CH(3)CCI(3) in the total atmosphere is 4.8 +/- 0.3 years, which is substantially lower than previously estimated. The deduced hydroxyl radical concentration, which measures the atmosphere's oxidizing capability, shows little change from 1978 to 1994.

A new species of Phoma causes ascochyta blight symptoms on field peas (Pisum sativum) in South Australia.

Phoma koolunga sp. nov. is described, having been isolated from ascochyta blight lesions on field pea (Pisum sativum) in South Australia. The species is described morphologically and sequences of the internal transcribed spacer region compared with those of the accepted pathogens causing ascochyta blight of field peas. P. koolunga was distinct from Mycosphaerella pinodes (anamorph: Ascochyta pinodes), Phoma medicaginis var. pinodella and Ascochyta pisi. Under controlled conditions the symptoms on pea seedlings caused by P. koolunga were indistinguishable from those caused by M. pinodes, other than a 24 h delay in disease development. Isolates of P. koolunga differed in the severity of disease caused on pea seedlings.

21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures.

We studied the protective efficacy of novel 21-aminosteroids against several forms of neuronal injury in murine cortical cell cultures. Concentrations of 200 nM to 20 microM partially attenuated the damage induced by glucose deprivation, combined oxygen-glucose deprivation, or exposure to NMDA; maximal protection was less than that produced by NMDA antagonists, but the combination of a 21-aminosteroid plus an NMDA antagonist produced a greater benefit than either drug alone. 21-Aminosteroid addition did not attenuate NMDA-induced whole-cell current, but did block almost all of the damage induced by exposure to iron, a protective action consistent with inhibition of free radical-mediated lipid peroxidation. Lipid peroxidation may be a downstream event mediating a portion of the injury triggered by excess stimulation of NMDA receptors.

AMPA receptor activation potentiates zinc neurotoxicity.

Extracellular Zn2+ attenuates NMDA receptor-mediated neurotoxicity and increases AMPA receptor-mediated toxicity. Known electrophysiological effects of Zn2+ predict only the former. We considered the possibility that the latter rather reflects AMPA potentiation of Zn2+ toxicity, perhaps mediated by neuronal depolarization and Zn2+ entry through voltage-gated Ca2+ channels. High K+ or kainate also potentiated Zn2+ toxicity, and AMPA plus Zn2+ toxicity was attenuated by raising extracellular Ca2+, or by Ca2+ channel blockers. AMPA plus Zn2+ exposure induced an increase in fluorescence from neurons loaded with the Zn(2+)-sensitive dye TS-Q and increased subsequent 45Ca2+ accumulation. The ability of AMPA receptor activation to potentiate Zn2+ toxicity may be relevant to neuronal death associated with intense activation of glutamatergic pathways.