Nucleophilic imine additions with vinyl organometallics have developed into efficient, high-yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the ...hydrozirconation/transmetalation/imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogues have been prepared on up to 160-g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II′ β-turn secondary structures and display impressive biological properties including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.
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We report on a search for compact binary coalescences where at least one binary component has a mass between 0.2 M_{⊙} and 1.0 M_{⊙} in Advanced LIGO and Advanced Virgo data collected between 1 ...April 2019 1500 UTC and 1 October 2019 1500 UTC. We extend our previous analyses in two main ways: we include data from the Virgo detector and we allow for more unequal mass systems, with mass ratio q≥0.1. We do not report any gravitational-wave candidates. The most significant trigger has a false alarm rate of 0.14 yr^{-1}. This implies an upper limit on the merger rate of subsolar binaries in the range 220-24200 Gpc^{-3} yr^{-1}, depending on the chirp mass of the binary. We use this upper limit to derive astrophysical constraints on two phenomenological models that could produce subsolar-mass compact objects. One is an isotropic distribution of equal-mass primordial black holes. Using this model, we find that the fraction of dark matter in primordial black holes in the mass range 0.2 M_{⊙}<m_{PBH}<1.0 M_{⊙} is f_{PBH}≡Ω_{PBH}/Ω_{DM}≲6%. This improves existing constraints on primordial black hole abundance by a factor of ∼3. The other is a dissipative dark matter model, in which fermionic dark matter can collapse and form black holes. The upper limit on the fraction of dark matter black holes depends on the minimum mass of the black holes that can be formed: the most constraining result is obtained at M_{min}=1 M_{⊙}, where f_{DBH}≡Ω_{DBH}/Ω_{DM}≲0.003%. These are the first constraints placed on dissipative dark models by subsolar-mass analyses.
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Alpine dwarf shrub communities are phenologically linked with snowmelt timing, so early spring exposure may increase risk of freezing damage during early development, and consequently reduce seasonal ...growth. We examined whether environmental factors (duration of snow cover, elevation) influenced size and the vulnerability of shrubs to spring freezing along elevational gradients and snow microhabitats by modelling the past frequency of spring freezing events. We sampled biomass and measured the size of Salix herbacea, Vaccinium myrtillus, Vaccinium uliginosum and Loiseleuria procumbens in late spring. Leaves were exposed to freezing temperatures to determine the temperature at which 50 % of specimens are killed for each species and sampling site. By linking site snowmelt and temperatures to long-term climate measurements, we extrapolated the frequency of spring freezing events at each elevation, snow microhabitat and per species over 37 years. Snowmelt timing was significantly driven by microhabitat effects, but was independent of elevation. Shrub growth was neither enhanced nor reduced by earlier snowmelt, but decreased with elevation. Freezing resistance was strongly species dependent, and did not differ along the elevation or snowmelt gradient. Microclimate extrapolation suggested that potentially lethal freezing events (in May and June) occurred for three of the four species examined. Freezing events never occurred on late snow beds, and increased in frequency with earlier snowmelt and higher elevation. Extrapolated freezing events showed a slight, non-significant increase over the 37-year record. We suggest that earlier snowmelt does not enhance growth in four dominant alpine shrubs, but increases the risk of lethal spring freezing exposure for less freezing-resistant species.
Interferometric gravitational-wave detectors are complex instruments comprised of a Michelson interferometer enhanced by multiple coupled cavities. Active feedback control is required to operate ...these instruments and keep the cavities locked on resonance. The optical response is highly nonlinear until a good operating point is reached. The linear operating range is between and 1% of a fringe for each degree of freedom. The resonance lock has to be achieved in all five degrees of freedom simultaneously, making the acquisition difficult. Furthermore, the cavity linewidth seen by the laser is only Hz, which is four orders of magnitude smaller than the linewidth of the free running laser. The arm length stabilization system is a new technique used for arm cavity locking in Advanced LIGO. Together with a modulation technique utilizing third harmonics to lock the central Michelson interferometer, the Advanced LIGO detector has been successfully locked and brought to an operating point where detecting gravitational-waves becomes feasible.
Background Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against ...MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma. Methods Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain–specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162. Results We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval CI = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162. Conclusion Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma.
Searches are under way in Advanced LIGO and Virgo data for persistent gravitational waves from continuous sources, e.g. rapidly rotating galactic neutron stars, and stochastic sources, e.g. relic ...gravitational waves from the Big Bang or superposition of distant astrophysical events such as mergers of black holes or neutron stars. These searches can be degraded by the presence of narrow spectral artifacts (lines) due to instrumental or environmental disturbances. We describe a variety of methods used for finding, identifying and mitigating these artifacts, illustrated with particular examples. Results are provided in the form of lists of line artifacts that can safely be treated as non-astrophysical. Such lists are used to improve the efficiencies and sensitivities of continuous and stochastic gravitational wave searches by allowing vetoes of false outliers and permitting data cleaning.
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Since their introduction in south-eastern France around 1999, new, 'emerging' (EM) strains of watermelon mosaic virus (WMV) coexist with the 'classic' (CL) strains present for more than 40 years. ...This situation constitutes a unique opportunity to estimate the frequency of recombinants appearing in the few years following introduction of new strains of a plant RNA virus. Molecular analyses performed on more than 1000 isolates from epidemiological surveys (2004-2008) and from experimental plots (2009-2010), and targeting only recombinants that became predominant in at least one plant, revealed at least seven independent CL/EM or EM/EM recombination events. The frequency of recombinants involving at least one EM parent in the natural populations tested was on the order of 1 %. No new recombinant was detected for more than 1 year, and none but one in more than one location. In tests comparing host range and aphid transmissibility, the new recombinants did not display a better fitness than their 'parental' isolates. No recombinant was detected from artificial mixed infections of CL and EM isolates of various hosts after testing more than 1500 subcultures obtained after single-aphid transmission. These results constitute one of the first estimations of the frequency of recombinants in natural conditions for a plant RNA virus. This suggests that although viable recombinants of WMV are not rare, and although recombination may potentially lead to new highly damaging strains, the new recombinants observed so far had a lower fitness than the parental strains and did not emerge durably in the populations.
Gravitational wave interferometers achieve their profound sensitivity by combining a Michelson interferometer with optical cavities, suspended masses, and now, squeezed quantum states of light. These ...states modify the measurement process of the LIGO, VIRGO and GEO600 interferometers to reduce the quantum noise that masks astrophysical signals; thus, improvements to squeezing are essential to further expand our gravitational view of the Universe. Further reducing quantum noise will require both lowering decoherence from losses as well more sophisticated manipulations to counter the quantum back-action from radiation pressure. Both tasks require fully understanding the physical interactions between squeezed light and the many components of km-scale interferometers. To this end, data from both LIGO observatories in observing run three are expressed using frequency-dependent metrics to analyze each detector's quantum response to squeezed states. The response metrics are derived and used to concisely describe physical mechanisms behind squeezing's simultaneous interaction with transverse-mode selective optical cavities and the quantum radiation pressure noise of suspended mirrors. These metrics and related analysis are broadly applicable for cavity-enhanced optomechanics experiments that incorporate external squeezing, and-for the first time-give physical descriptions of every feature so far observed in the quantum noise of the LIGO detectors.
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