Stereospecific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in <i>ESR1</i> Mutant Breast Cancer Cells

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene derivatives that maintained the drug’s antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles. SIGNIFICANCE This study shows that antiestrogens that enforce a wild-type-like estrogen receptor alpha antagonist conformation demonstrate improved therapeutic activities in hormone-resistant breast cancer cells harboring activating Y537S ESR1 mutant

Methane Throughout the Atmosphere of the Warm Exoplanet WASP-80b

The abundances of major carbon and oxygen bearing gases in the atmospheres of giant exoplanets provide insights into atmospheric chemistry and planet formation processes. Thermochemistry suggests that methane should be the dominant carbon-bearing species below $\sim$1000 K over a range of plausible atmospheric compositions; this is the case for the Solar System planets and has been confirmed in the atmospheres of brown dwarfs and self-luminous directly imaged exoplanets. However, methane has not yet been definitively detected with space-based spectroscopy in the atmosphere of a transiting exoplanet, but a few detections have been made with ground-based, high-resolution transit spectroscopy including a tentative detection for WASP-80b. Here we report transmission and emission spectra spanning 2.4-4.0 micrometers of the 825 K warm Jupiter WASP-80b taken with JWST's NIRCam instrument, both of which show strong evidence for methane at greater than 6-sigma significance. The derived methane abundances from both viewing geometries are consistent with each other and with solar to sub-solar C/O and ~5$\times$ solar metallicity, which is consistent with theoretical predictions.Comment: 23 pages, 10 figures, 3 tables. This preprint has been submitted to and accepted in principle for publication in Nature without significant change

Estimating the infection-fatality risk of SARS-CoV-2 in New York City during the spring 2020 pandemic wave: a model-based analysis

Background As the COVID-19 pandemic continues to unfold, the infection-fatality risk (ie, risk of death among all infected individuals including those with asymptomatic and mild infections) is crucial for gauging the burden of death due to COVID-19 in the coming months or years. Here, we estimate the infection-fatality risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in New York City, NY, USA, the first epidemic centre in the USA, where the infection-fatality risk remains unclear. Methods In this model-based analysis, we developed a meta-population network model-inference system to estimate the underlying SARS-CoV-2 infection rate in New York City during the 2020 spring pandemic wave using available case, mortality, and mobility data. Based on these estimates, we further estimated the infection-fatality risk for all ages overall and for five age groups (<25, 25–44, 45–64, 65–74, and ≥75 years) separately, during the period March 1 to June 6, 2020 (ie, before the city began a phased reopening). Findings During the period March 1 to June 6, 2020, 205 639 people had a laboratory-confirmed infection with SARS-CoV-2 and 21 447 confirmed and probable COVID-19-related deaths occurred among residents of New York City. We estimated an overall infection-fatality risk of 1·39% (95% credible interval 1·04–1·77) in New York City. Our estimated infection-fatality risk for the two oldest age groups (65–74 and ≥75 years) was much higher than the younger age groups, with a cumulative estimated infection-fatality risk of 0·116% (0·0729–0·148) for those aged 25–44 years and 0·939% (0·729–1·19) for those aged 45–64 years versus 4·87% (3·37–6·89) for those aged 65–74 years and 14·2% (10·2–18·1) for those aged 75 years and older. In particular, weekly infection-fatality risk was estimated to be as high as 6·72% (5·52–8·01) for those aged 65–74 years and 19·1% (14·7–21·9) for those aged 75 years and older. Interpretation Our results are based on more complete ascertainment of COVID-19-related deaths in New York City than other places and thus probably reflect the true higher burden of death due to COVID-19 than that previously reported elsewhere. Given the high infection-fatality risk of SARS-CoV-2, governments must account for and closely monitor the infection rate and population health outcomes and enact prompt public health responses accordingly as the COVID-19 pandemic unfolds

The BCN Challenge to Compatibilist Free Will and Personal Responsibility

Many philosophers ignore developments in the behavioral, cognitive, and neurosciences that purport to challenge our ideas of free will and responsibility. The reason for this is that the challenge is often framed as a denial of the idea that we are able to act differently than we do. However, most philosophers think that the ability to do otherwise is irrelevant to responsibility and free will. Rather it is our ability to act for reasons that is crucial. We argue that the scientific findings indicate that it is not so obvious that our views of free will and responsibility can be grounded in the ability to act for reasons without introducing metaphysical obscurities. This poses a challenge to philosophers. We draw the conclusion that philosophers are wrong not to address the recent scientific developments and that scientists are mistaken in formulating their challenge in terms of the freedom to do otherwise

The Pandora SmallSat: Multiwavelength Characterization of Exoplanets and their Host Stars

Pandora is a SmallSat mission concept, selected as part of NASA’s Astrophysics Pioneers Program, designed to study the atmospheres of exoplanets using transmission spectroscopy. Transmission spectroscopy of transiting exoplanets provides our best opportunity to identify the makeup of planetary atmospheres in the coming decade. Stellar brightness variations due to star spots, however, can seep into these measurements and contaminate the observed spectra. Pandora is designed to disentangle star and planet signals in transmission spectra and reliably characterize the planetary atmospheres. Pandora will collect long-duration photometric observations with a visible-light channel, and simultaneous spectra with a near-IR channel, where water is a strong molecular absorber. The broad wavelength coverage will provide constraints on spot covering fractions of the stars and determine the impact of these active regions on the planetary spectra. Pandora will observe at least 20 exoplanets with sizes ranging from Earth-size to Jupiter-size, with host stars spanning mid-K to late-M spectral types. The project is made possible by leveraging investments in other projects, including an all-aluminum 0.45-meter Cassegrain telescope design, and an IR sensor chip assembly from the James Webb Space Telescope. The mission will last five years from initial formulation to closeout, with one-year of science operations. Launch is planned for the mid-2020s as a secondary payload in Sun-synchronous low-Earth orbit. By design, Pandora has a diverse team, with over half of mission leadership roles filled by early career scientists and engineers, demonstrating the high value of SmallSats for developing the next generation of space mission leaders

Bioactive Endophytes Warrant Intensified Exploration and Conservation

A key argument in favor of conserving biodiversity is that as yet undiscovered biodiversity will yield products of great use to humans. However, the link between undiscovered biodiversity and useful products is largely conjectural. Here we provide direct evidence from bioassays of endophytes isolated from tropical plants and bioinformatic analyses that novel biology will indeed yield novel chemistry of potential value.We isolated and cultured 135 endophytic fungi and bacteria from plants collected in Peru. nrDNAs were compared to samples deposited in GenBank to ascertain the genetic novelty of cultured specimens. Ten endophytes were found to be as much as 15–30% different than any sequence in GenBank. Phylogenetic trees, using the most similar sequences in GenBank, were constructed for each endophyte to measure phylogenetic distance. Assays were also conducted on each cultured endophyte to record bioactivity, of which 65 were found to be bioactive.The novelty of our contribution is that we have combined bioinformatic analyses that document the diversity found in environmental samples with culturing and bioassays. These results highlight the hidden hyperdiversity of endophytic fungi and the urgent need to explore and conserve hidden microbial diversity. This study also showcases how undergraduate students can obtain data of great scientific significance

A Serological Survey of Infectious Disease in Yellowstone National Park’s Canid Community

BACKGROUND:Gray wolves (Canis lupus) were reintroduced into Yellowstone National Park (YNP) after a >70 year absence, and as part of recovery efforts, the population has been closely monitored. In 1999 and 2005, pup survival was significantly reduced, suggestive of disease outbreaks. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed sympatric wolf, coyote (Canis latrans), and red fox (Vulpes vulpes) serologic data from YNP, spanning 1991-2007, to identify long-term patterns of pathogen exposure, identify associated risk factors, and examine evidence for disease-induced mortality among wolves for which there were survival data. We found high, constant exposure to canine parvovirus (wolf seroprevalence: 100%; coyote: 94%), canine adenovirus-1 (wolf pups [0.5-0.9 yr]: 91%, adults [>or=1 yr]: 96%; coyote juveniles [0.5-1.5 yrs]: 18%, adults [>or=1.6 yrs]: 83%), and canine herpesvirus (wolf: 87%; coyote juveniles: 23%, young adults [1.6-4.9 yrs]: 51%, old adults [>or=5 yrs]: 87%) suggesting that these pathogens were enzootic within YNP wolves and coyotes. An average of 50% of wolves exhibited exposure to the protozoan parasite, Neospora caninum, although individuals' odds of exposure tended to increase with age and was temporally variable. Wolf, coyote, and fox exposure to canine distemper virus (CDV) was temporally variable, with evidence for distinct multi-host outbreaks in 1999 and 2005, and perhaps a smaller, isolated outbreak among wolves in the interior of YNP in 2002. The years of high wolf-pup mortality in 1999 and 2005 in the northern region of the park were correlated with peaks in CDV seroprevalence, suggesting that CDV contributed to the observed mortality. CONCLUSIONS/SIGNIFICANCE:Of the pathogens we examined, none appear to jeopardize the long-term population of canids in YNP. However, CDV appears capable of causing short-term population declines. Additional information on how and where CDV is maintained and the frequency with which future epizootics might be expected might be useful for future management of the Northern Rocky Mountain wolf population

Scanning Angle Plasmon Waveguide Resonance Raman Spectroscopy for the Analysis of Thin Polystyrene Films

Scanning angle (SA) Raman spectroscopy was used to characterize thin polymer films at a sapphire/50 nm gold film/polystyrene/air interface. When the polymer thickness is greater than ∼260 nm, this interface behaves as a plasmon waveguide; Raman scatter is greatly enhanced with both p- and s-polarized excitation compared to an interface without the gold film. In this study, the reflected light intensities from the interface and Raman spectra were collected as a function of incident angle for three samples with different polystyrene thicknesses. The Raman peak areas were well modeled with the calculated mean-square electric field (MSEF) integrated over the polymer film at varying incident angles. A 412 nm polystyrene plasmon waveguide generated 3.34× the Raman signal at 40.52° (the plasmon waveguide resonance angle) compared to the signal measured at 70.4° (the surface plasmon resonance angle). None of the studied polystyrene plasmon waveguides produced detectable Raman scatter using a 180° backscatter collection geometry, demonstrating the sensitivity of the SA Raman technique. The data highlight the ability to measure polymer thickness, chemical content, and, when combined with calculations of MSEF as a function of distance from the interface, details of polymer structure and order. The SA Raman spectroscopy thickness measurements agreed with those obtained from optical interferometery with an average difference of 2.6%. This technique has the potential to impact the rapidly developing technologies utilizing metal/polymer films for energy storage and electronic devices

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management