Hydrogen sulfide and metal-enriched atmosphere for a Jupiter-mass exoplanet.

As the closest transiting hot Jupiter to Earth, HD 189733b has been the benchmark planet for atmospheric characterization 1,2,3. It has also been the anchor point for much of our theoretical understanding of exoplanet atmospheres from composition 4, chemistry 5,6, aerosols 7 to atmospheric dynamics 8, escape 9 and modeling techniques 10,11. Prior studies of HD 189733b have detected carbon and oxygen-bearing molecules H2O and CO 12,13 in the atmosphere. The presence of CO2 and CH4 has been claimed 14,15 but later disputed 12,16,17. The inferred metallicity based on these measurements, a key parameter in tracing planet formation locations 18, varies from depletion 19,20 to enhancement 21,22, hindered by limited wavelength coverage and precision of the observations. Here we report detections of H2O (13.4 sigma), CO2 (11.2 sigma), CO (5 sigma), and H2S (4.5 sigma) in the transmission spectrum (2.4-5 micron) of HD 189733b. With an equilibrium temperature of ~ 1200K, H2O, CO, and H2S are the main reservoirs for oxygen, carbon, and sulfur. Based on the measured abundances of these three major volatile elements, we infer an atmospheric metallicity of 3-5 times stellar. The upper limit on the methane abundance at 5 sigma is 0.1 ppm which indicates a low carbon-to-oxygen ratio (<0.2), suggesting formation through the accretion of water-rich icy planetesimals. The low oxygen-to-sulfur and carbon-to-sulfur ratios also support the planetesimal accretion formation pathway 23.

A high internal heat flux and large core in a warm Neptune exoplanet.

Interactions between exoplanetary atmospheres and internal properties have long been proposed to be drivers of the inflation mechanisms of gaseous planets and apparent atmospheric chemical disequilibrium conditions1. However, transmission spectra of exoplanets have been limited in their ability to observationally confirm these theories owing to the limited wavelength coverage of the Hubble Space Telescope (HST) and inferences of single molecules, mostly H2O (ref. 2). In this work, we present the panchromatic transmission spectrum of the approximately 750 K, low-density, Neptune-sized exoplanet WASP-107b using a combination of HST Wide Field Camera 3 (WFC3) and JWST Near-Infrared Camera (NIRCam) and Mid-Infrared Instrument (MIRI). From this spectrum, we detect spectroscopic features resulting from H2O (21σ), CH4 (5σ), CO (7σ), CO2 (29σ), SO2 (9σ) and NH3 (6σ). The presence of these molecules enables constraints on the atmospheric metal enrichment (M/H is 10-18× solar3), vertical mixing strength (log10Kzz = 8.4-9.0 cm2 s-1) and internal temperature (>345 K). The high internal temperature is suggestive of tidally driven inflation4 acting on a Neptune-like internal structure, which can naturally explain the large radius and low density of the planet. These findings suggest that eccentricity-driven tidal heating is a critical process governing atmospheric chemistry and interior-structure inferences for most of the cool (<1,000 K) super-Earth-to-Saturn-mass exoplanet population.

Development of a sterile insect technique as a control strategy for the Asian citrus psyllid: establishing the effect of sterilizing X-rays on fecundity, fertility, and survival.

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is a major pest of citrus due to its role as the vector of the bacterium that causes huanglongbing. In commercial citrus, ACP control currently relies on the application of insecticides, which may not be sustainable long-term, nor practical in urban areas. The sterile insect technique (SIT) is an alternative strategy in which large numbers of pests are reared, sterilized using radiation, and then released into the field to compete with wild individuals for matings, suppressing population growth. As a fundamental step toward the development of SIT for ACP, this study sought to identify the optimum radiation dose required to sterilize ACP without affecting their survival and mating capacity. Virgin adult ACP of both sexes were subjected to doses of X-ray irradiation ranging from 40 to 480 Gy, then paired with a nonirradiated mate and allowed to produce offspring. Fecundity was estimated as the number of eggs laid, and fertility as the proportion of those eggs that hatched. Females were more radio-sensitive than males, exhibiting a major drop in fecundity at even the lowest dose and 100% sterility at 80 Gy. In contrast, a fivefold higher dose (400 Gy) did not achieve complete sterility in males, with around 5% offspring survival. However, F1 progeny of males exposed to 320 Gy or higher were subsequently found to be 100% sterile. This confirmation of inherited sterility suggests that balancing the sterilizing effects of radiation against its mortality-inducing effects may warrant further evaluation.

SO2, silicate clouds, but no CH4 detected in a warm Neptune.

WASP-107b is a warm (approximately 740 K) transiting planet with a Neptune-like mass of roughly 30.5 M⊕ and Jupiter-like radius of about 0.94 RJ (refs. 1,2), whose extended atmosphere is eroding3. Previous observations showed evidence for water vapour and a thick, high-altitude condensate layer in the atmosphere of WASP-107b (refs. 4,5). Recently, photochemically produced sulfur dioxide (SO2) was detected in the atmosphere of a hot (about 1,200 K) Saturn-mass planet from transmission spectroscopy near 4.05 µm (refs. 6,7), but for temperatures below about 1,000 K, sulfur is predicted to preferably form sulfur allotropes instead of SO2 (refs. 8-10). Here we report the 9σ detection of two fundamental vibration bands of SO2, at 7.35 µm and 8.69 µm, in the transmission spectrum of WASP-107b using the Mid-Infrared Instrument (MIRI) of JWST. This discovery establishes WASP-107b as the second irradiated exoplanet with confirmed photochemistry, extending the temperature range of exoplanets exhibiting detected photochemistry from about 1,200 K down to about 740 K. Furthermore, our spectral analysis reveals the presence of silicate clouds, which are strongly favoured (around 7σ) over simpler cloud set-ups. Furthermore, water is detected (around 12σ) but methane is not. These findings provide evidence of disequilibrium chemistry and indicate a dynamically active atmosphere with a super-solar metallicity.

Methane throughout the atmosphere of the warm exoplanet WASP-80b.

The abundances of main carbon- and oxygen-bearing gases in the atmospheres of giant exoplanets provide insights into atmospheric chemistry and planet formation processes1,2. Thermochemistry suggests that methane (CH4) should be the dominant carbon-bearing species below about 1,000 K over a range of plausible atmospheric compositions3; this is the case for the solar system planets4 and has been confirmed in the atmospheres of brown dwarfs and self-luminous, directly imaged exoplanets5. However, CH4 has not yet been definitively detected with space-based spectroscopy in the atmosphere of a transiting exoplanet6-11, but a few detections have been made with ground-based, high-resolution transit spectroscopy12,13 including a tentative detection for WASP-80b (ref. 14). Here we report transmission and emission spectra spanning 2.4-4.0 µm of the 825 K warm Jupiter WASP-80b taken with the NIRCam instrument of the JWST, both of which show strong evidence of CH4 at greater than 6σ significance. The derived CH4 abundances from both viewing geometries are consistent with each other and with solar to sub-solar C/O and around five times solar metallicity, which is consistent with theoretical predictions15-17.

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells.

A series of novel 3-(prop-1-en-2-yl)azetidin-2-one, 3-allylazetidin-2-one and 3-(buta-1,3-dien-1-yl)azetidin-2-one analogues of combretastatin A-4 (CA-4) were designed and synthesised as colchicine-binding site inhibitors (CBSI) in which the ethylene bridge of CA-4 was replaced with a ß-lactam (2-azetidinone) scaffold. These compounds, together with related prodrugs, were evaluated for their antiproliferative activity, cell cycle effects and ability to inhibit tubulin assembly. The compounds demonstrated significant in vitro antiproliferative activities in MCF-7 breast cancer cells, particularly for compounds 9h, 9q, 9r, 10p, 10r and 11h, with IC50 values in the range 10-33 nM. These compounds were also potent in the triple-negative breast cancer (TBNC) cell line MDA-MB-231, with IC50 values in the range 23-33 nM, and were comparable with the activity of CA-4. The compounds inhibited the polymerisation of tubulin in vitro, with significant reduction in tubulin polymerization, and were shown to interact at the colchicine-binding site on tubulin. Flow cytometry demonstrated that compound 9q arrested MCF-7 cells in the G2/M phase and resulted in cellular apoptosis. The antimitotic properties of 9q in MCF-7 human breast cancer cells were also evaluated, and the effect on the organization of microtubules in the cells after treatment with compound 9q was observed using confocal microscopy. The immunofluorescence results confirm that ß-lactam 9q is targeting tubulin and resulted in mitotic catastrophe in MCF-7 cells. In silico molecular docking supports the hypothesis that the compounds interact with the colchicine-binding domain of tubulin. Compound 9q is a novel potent microtubule-destabilising agent with potential as a promising lead compound for the development of new antitumour agents.

A phase I, first-in-human study investigating the safety, tolerability, and pharmacokinetics of the maturation inhibitor GSK3739937.

We report the safety and pharmacokinetic properties of the HIV-1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first-in-human, double-blind, randomized, placebo-controlled, single- (part 1) and multiple- (part 2) dose escalation study with an additional open-label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10-800 mg) in part 1, up to 18 once-daily 25- to 100-mg or 3 once-weekly 500-mg doses in part 2, and single 100-mg doses as powder-in-bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety-one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug-related AEs were gastrointestinal (14/17, 82%). The terminal phase half-life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose-proportional increases during part 1. Accumulation in exposure following repeat dosing was 6- to 7-fold with daily dosing and ~1.7-fold after weekly treatment, as expected due to the long half-life. Bioavailability of GSK'937 after a meal was 1.35- to 1.40-fold greater as a tablet versus powder-in-bottle and >2-fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose-limiting safety events occurred. Pharmacokinetic parameters of long half-life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.

Thermal emission from the Earth-sized exoplanet TRAPPIST-1 b using JWST.

The TRAPPIST-1 system is remarkable for its seven planets that are similar in size, mass, density and stellar heating to the rocky planets Venus, Earth and Mars in the Solar System1. All the TRAPPIST-1 planets have been observed with transmission spectroscopy using the Hubble or Spitzer space telescopes, but no atmospheric features have been detected or strongly constrained2-5. TRAPPIST-1 b is the closest planet to the M-dwarf star of the system, and it receives four times as much radiation as Earth receives from the Sun. This relatively large amount of stellar heating suggests that its thermal emission may be measurable. Here we present photometric secondary eclipse observations of the Earth-sized exoplanet TRAPPIST-1 b using the F1500W filter of the mid-infrared instrument on the James Webb Space Telescope (JWST). We detect the secondary eclipses in five separate observations with 8.7σ confidence when all data are combined. These measurements are most consistent with re-radiation of the incident flux of the TRAPPIST-1 star from only the dayside hemisphere of the planet. The most straightforward interpretation is that there is little or no planetary atmosphere redistributing radiation from the host star and also no detectable atmospheric absorption of carbon dioxide (CO2) or other species.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4.

Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-ß-lactams and 3,3-dichloro-ß-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that ß-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-ß-lactams and the amino acid residues of the colchicine binding active site cavity of ß-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

Quality of Life in Patients With Heart Failure With Recovered Ejection Fraction.

Importance: Heart failure with recovered ejection fraction (HFrecEF) is a recently recognized phenotype of patients with a history of reduced left ventricular ejection fraction (LVEF) that has subsequently normalized. It is unknown whether such LVEF improvement is associated with improvements in health status. Objective: To examine changes in health-related quality of life in patients with heart failure with reduced ejection fraction (HFrEF) whose LVEF normalized, compared with those whose LVEF remains reduced and those with HF with preserved EF (HFpEF). Design, Setting, and Participants: This prospective cohort study was conducted at a tertiary care hospital from November 2016 to December 2018. Consecutive patients seen in a heart failure clinic who completed patient-reported outcome assessments were included. Clinical data were abstracted from the electronic health record. Data analysis was completed from February to December 2020. Main Outcomes and Measures: Changes in Kansas City Cardiomyopathy Questionnaire overall summary score, Visual Analog Scale score, and Patient-Reported Outcomes Measurement Information System domain scores on physical function, fatigue, depression, and satisfaction with social roles over 1-year follow-up. Results: The study group included 319 patients (mean [SD] age, 60.4 [15.5] years; 120 women [37.6%]). At baseline, 212 patients (66.5%) had HFrEF and 107 (33.5%) had HFpEF. At a median follow-up of 366 (interquartile range, 310-421) days, LVEF had increased to 50% or more in 35 patients with HFrEF (16.5%). Recovery of systolic function was associated with heart failure-associated quality-of-life improvement, such that for each 10% increase in LVEF, the Kansas City Cardiomyopathy Questionnaire score improved by an mean (SD) of 4.8 (1.6) points (P = .003). Recovery of LVEF was also associated with improvement of physical function, satisfaction with social roles, and a reduction in fatigue. Conclusions and Relevance: Among patients with HFrEF in this study, normalization of left ventricular systolic function was associated with a significant improvement in health-related quality of life.

Successes and insights of an industry biotech program to enhance maize agronomic traits.

Corteva Agriscience™ ran a discovery research program to identify biotech leads for improving maize Agronomic Traits such as yield, drought tolerance, and nitrogen use efficiency. Arising from many discovery sources involving thousands of genes, this program generated over 3331 DNA cassette constructs involving a diverse set of circa 1671 genes, whose transformed maize events were field tested from 2000 to 2018 under managed environments designed to evaluate their potential for commercialization. We demonstrate that a subgroup of these transgenic events improved yield in field-grown elite maize breeding germplasm. A set of at least 22 validated gene leads are identified and described which represent diverse molecular and physiological functions. These leads illuminate sectors of biology that could guide crop improvement in maize and perhaps other crops. In this review and interpretation, we share some of our approaches and results, and key lessons learned in discovering and developing these maize Agronomic Traits leads.

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

AIMS: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. RESULTS: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.

A machine learning compatible method for ordinal propensity score stratification and matching.

Although machine learning techniques that estimate propensity scores for observational studies with multivalued treatments have advanced rapidly in recent years, the development of propensity score adjustment techniques has not kept pace. While machine learning propensity models provide numerous benefits, they do not produce a single variable balancing score that can be used for propensity score stratification and matching. This issue motivates the development of a flexible ordinal propensity scoring methodology that does not require parametric assumptions for the propensity model. The proposed method fits a one-parameter power function to the cumulative distribution function (CDF) of the generalized propensity score (GPS) vector resulting from any machine learning propensity model, and is henceforth called the GPS-CDF method. The estimated parameter from the GPS-CDF method, ã , is a scalar balancing score that can be used to group similar subjects in outcome analyses. Specifically, subjects who received different levels of the treatment are stratified or matched based on their ã value to produce unbiased estimates of the average treatment effect (ATE). Simulation studies presented show remediation of covariate balance, minimal bias in ATEs, and maintain coverage probability. The proposed method is applied to the Mexican-American Tobacco use in Children (MATCh) study to determine whether an ordinal treatment of exposure to smoking imagery in movies causes cigarette experimentation in Mexican-American adolescents.

Propensity score stratification methods for continuous treatments.

Continuous treatments propensity scoring remains understudied as the majority of methods are focused on the binary treatment setting. Current propensity score methods for continuous treatments typically rely on weighting in order to produce causal estimates. It has been shown that in some continuous treatment settings, weighting methods can result in worse covariate balance than had no adjustments been made to the data. Furthermore, weighting is not always stable, and resultant estimates may be unreliable due to extreme weights. These issues motivate the current development of novel propensity score stratification techniques to be used with continuous treatments. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) and the nonparametric GPS-CDF approaches are introduced. Empirical CDFs are used to stratify subjects based on pretreatment confounders in order to produce causal estimates. A detailed simulation study shows superiority of these new stratification methods based on the empirical CDF, when compared with standard weighting techniques. The proposed methods are applied to the "Mexican-American Tobacco use in Children" study to determine the causal relationship between continuous exposure to smoking imagery in movies, and smoking behavior among Mexican-American adolescents. These promising results provide investigators with new options for implementing continuous treatment propensity scoring.

Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor.

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.

Knockouts of a late flowering gene via CRISPR-Cas9 confer early maturity in rice at multiple field locations.

KEY MESSAGE: OsGhd7 gene was discovered by screening our rice activation tagging population. CRISPR-Cas9 created knockouts of OsGhd7 conferred early flowering and early maturity in rice varieties across multiple geographical locations in China. Our research shows that OsGhd7 is a good target for breeding early maturity rice varieties, and an excellent example of the advantages of applying the CRISPR-Cas9 technology for trait improvement. Flowering time (heading date) is an important trait for crop cultivation and yield. In this study, we discovered a late flowering gene OsGhd7 by screening our rice activation tagging population, and demonstrated that overexpression of OsGhd7 delayed flowering time in rice, and the delay in flowering time depended on the transgene expression level. OsGhd7 is a functional allele of the Ghd7 gene family; knockouts of OsGhd7 generated by CRISPR-Cas9 significantly accelerated flowering time and the earliness of the flowering time depended on field location. The homozygous OsGhd7 knockout lines showed approximately 8, 10, and 20 days earlier flowering than controls at three different locations in China (Changsha City, Sanya City, and Beijing City, respectively) that varied from 18.25° N to 39.90° N. Furthermore, knockouts of OsGhd7 also showed an early flowering phenotype in different rice varieties, indicating OsGhd7 can be used as a common target gene for using the CRISPR technology to modulate rice flowering time. The importance of OsGhd7 and CRISPR technology for breeding early maturity rice varieties are discussed.

A novel approach for propensity score matching and stratification for multiple treatments: Application to an electronic health record-derived study.

Currently, methods for conducting multiple treatment propensity scoring in the presence of high-dimensional covariate spaces that result from "big data" are lacking-the most prominent method relies on inverse probability treatment weighting (IPTW). However, IPTW only utilizes one element of the generalized propensity score (GPS) vector, which can lead to a loss of information and inadequate covariate balance in the presence of multiple treatments. This limitation motivates the development of a novel propensity score method that uses the entire GPS vector to establish a scalar balancing score that, when adjusted for, achieves covariate balance in the presence of potentially high-dimensional covariates. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) method is introduced. A one-parameter power function fits the CDF of the GPS vector and a resulting scalar balancing score is used for matching and/or stratification. Simulation results show superior performance of the new method compared to IPTW both in achieving covariate balance and estimating average treatment effects in the presence of multiple treatments. The proposed approach is applied to a study derived from electronic medical records to determine the causal relationship between three different vasopressors and mortality in patients with non-traumatic aneurysmal subarachnoid hemorrhage. Results suggest that the GPS-CDF method performs well when applied to large observational studies with multiple treatments that have large covariate spaces.

Superior field performance of waxy corn engineered using CRISPR-Cas9.

We created waxy corn hybrids by CRISPR-Cas9 editing of a waxy allele in 12 elite inbred maize lines, a process that was more than a year faster than conventional trait introgression using backcrossing and marker-assisted selection. Field trials at 25 locations showed that CRISPR-waxy hybrids were agronomically superior to introgressed hybrids, producing on average 5.5 bushels per acre higher yield.