Yield stability is fundamental to global food security in the face of climate change, and better strategies are needed for buffering crop yields against increased weather variability. Regional- scale ...analyses of yield stability can support robust inferences about buffering strategies for widely-grown staple crops, but have not been accomplished. We present a novel analytical approach, synthesizing 2000-2014 data on weather and soil factors to quantify their impact on county-level maize yield stability in four US states that vary widely in these factors (Illinois, Michigan, Minnesota and Pennsylvania). Yield stability is quantified as both 'downside risk' (minimum yield potential, MYP) and 'volatility' (temporal yield variability). We show that excessive heat and drought decreased mean yields and yield stability, while higher precipitation increased stability. Soil water holding capacity strongly affected yield volatility in all four states, either directly (Minnesota and Pennsylvania) or indirectly, via its effects on MYP (Illinois and Michigan). We infer that factors contributing to soil water holding capacity can help buffer maize yields against variable weather. Given that soil water holding capacity responds (within limits) to agronomic management, our analysis highlights broadly relevant management strategies for buffering crop yields against climate variability, and informs region-specific strategies.
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated ...with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer, particularly when combined with carboplatin.
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•Fasnall is a thiophenopyrimidine targeting fatty acid synthase•Fasnall has anti-proliferative activity and induces apoptosis in breast cancer cells•Fasnall promotes fatty acid uptake, ceramide and diacylglycerol accumulation•Fasnall is well tolerated and shows efficacy against HER2+ breast tumors in vivo
Many tumors are dependent on de novo fatty acid synthesis. Using a chemoproteomic screen, Alwarawrah et al. identified Fasnall, a thiophenopyrimidine fatty acid synthase inhibitor that displays anti-neoplastic activity against breast cancer in vitro and in vivo.
The transition from medical school to residency is a critical step in the careers of physicians. Because of the standardized application process-wherein schools submit summative Medical Student ...Performance Evaluations (MSPE's)-it also represents a unique opportunity to assess the possible prevalence of racial and gender disparities, as shown elsewhere in medicine.
The authors conducted textual analysis of MSPE's from 6,000 US students applying to 16 residency programs at a single institution in 2014-15. They used custom software to extract demographic data and keyword frequency from each MSPE. The main outcome measure was the proportion of applicants described using 24 pre-determined words from four thematic categories ("standout traits", "ability", "grindstone habits", and "compassion").
The data showed significant differences based on race and gender. White applicants were more likely to be described using "standout" or "ability" keywords (including "exceptional", "best", and "outstanding") while Black applicants were more likely to be described as "competent". These differences remained significant after controlling for United States Medical Licensing Examination Step 1 scores. Female applicants were more frequently described as "caring", "compassionate", and "empathic" or "empathetic". Women were also more frequently described as "bright" and "organized".
While the MSPE is intended to reflect an objective, summative assessment of students' qualifications, these data demonstrate for the first time systematic differences in how candidates are described based on racial/ethnic and gender group membership. Recognizing possible implicit biases and their potential impact is important for faculty who strive to create a more egalitarian medical community.
The flavonoid pathway is one of the best characterized specialized metabolite pathways of plants. In angiosperms, the flavonoids have varied roles in assisting with tolerance to abiotic stress and ...are also key for signaling to pollinators and seed dispersal agents. The pathway is thought to be specific to land plants and to have arisen during the period of land colonization around 550-470 million years ago. In this review we consider current knowledge of the flavonoid pathway in the bryophytes, consisting of the liverworts, hornworts, and mosses. The pathway is less characterized for bryophytes than angiosperms, and the first genetic and molecular studies on bryophytes are finding both commonalities and significant differences in flavonoid biosynthesis and pathway regulation between angiosperms and bryophytes. This includes biosynthetic pathway branches specific to each plant group and the apparent complete absence of flavonoids from the hornworts.
Coral reefs feed millions of people worldwide, provide coastal protection and generate billions of dollars annually in tourism revenue. The underlying architecture of a reef is a biogenic carbonate ...structure that accretes over many years of active biomineralization by calcifying organisms, including corals and algae. Ocean acidification poses a chronic threat to coral reefs by reducing the saturation state of the aragonite mineral of which coral skeletons are primarily composed, and lowering the concentration of carbonate ions required to maintain the carbonate reef. Reduced calcification, coupled with increased bioerosion and dissolution, may drive reefs into a state of net loss this century. Our ability to predict changes in ecosystem function and associated services ultimately hinges on our understanding of community- and ecosystem-scale responses. Past research has primarily focused on the responses of individual species rather than evaluating more complex, community-level responses. Here we use an in situ carbon dioxide enrichment experiment to quantify the net calcification response of a coral reef flat to acidification. We present an estimate of community-scale calcification sensitivity to ocean acidification that is, to our knowledge, the first to be based on a controlled experiment in the natural environment. This estimate provides evidence that near-future reductions in the aragonite saturation state will compromise the ecosystem function of coral reefs.
Arctic terrestrial ecosystems are major global sources of methane (CH₄); hence, it is important to understand the seasonal and climatic controls on CH₄ emissions from these systems. Here, we report ...year-round CH₄ emissions from Alaskan Arctic tundra eddy flux sites and regional fluxes derived from aircraft data. We find that emissions during the cold season (September to May) account for ≥50% of the annual CH₄ flux, with the highest emissions from noninundated upland tundra. A major fraction of cold season emissions occur during the “zero curtain” period, when subsurface soil temperatures are poised near 0 °C. The zero curtain may persist longer than the growing season, and CH₄ emissions are enhanced when the duration is extended by a deep thawed layer as can occur with thick snow cover. Regional scale fluxes of CH₄ derived from aircraft data demonstrate the large spatial extent of late season CH₄ emissions. Scaled to the circumpolar Arctic, cold season fluxes from tundra total 12 ± 5 (95% confidence interval) Tg CH₄ y⁻¹, ∼25% of global emissions from extratropical wetlands, or ∼6% of total global wetland methane emissions. The dominance of late-season emissions, sensitivity to soil environmental conditions, and importance of dry tundra are not currently simulated in most global climate models. Because Arctic warming disproportionally impacts the cold season, our results suggest that higher cold-season CH₄ emissions will result from observed and predicted increases in snow thickness, active layer depth, and soil temperature, representing important positive feedbacks on climate warming.
Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is ...predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.
Globally increasing sea surface temperatures threaten coral reefs, both directly and through interactions with local stressors. More resilient reefs have a higher likelihood of returning to a ...coral-dominated state following a disturbance, such as a mass bleaching event. To advance practical approaches to reef resilience assessments and aid resilience-based management of coral reefs, we conducted a resilience assessment for Puerto Rico's coral reefs, modified from methods used in other U.S. jurisdictions. We calculated relative resilience scores for 103 sites from an existing commonwealth-wide survey using eight resilience indicators-such as coral diversity, macroalgae percent cover, and herbivorous fish biomass-and assessed which indicators most drove resilience. We found that sites of very different relative resilience were generally highly spatially intermixed, underscoring the importance and necessity of decision making and management at fine scales. In combination with information on levels of two localized stressors (fishing pressure and pollution exposure), we used the resilience indicators to assess which of seven potential management actions could be used at each site to maintain or improve resilience. Fishery management was the management action that applied to the most sites. Furthermore, we combined sites' resilience scores with projected ocean warming to assign sites to vulnerability categories. Island-wide or community-level managers can use the actions and vulnerability information as a starting point for resilience-based management of their reefs. This assessment differs from many previous ones because we tested how much information could be yielded by a "desktop" assessment using freely-available, existing data rather than from a customized, resilience-focused field survey. The available data still permitted analyses comparable to previous assessments, demonstrating that desktop resilience assessments can substitute for assessments with field components under some circumstances.
Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years.
To estimate quality-adjusted life-years lost due to obesity and knee ...osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago.
The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group.
United States.
U.S. population aged 50 to 84 years.
Quality-adjusted life-years lost owing to knee osteoarthritis and obesity.
Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178,071 cases of coronary heart disease, 889,872 cases of diabetes, and 111,206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6,318,030 years and improve life expectancy by 7,812,120 quality-adjusted years in U.S. adults aged 50 to 84 years.
Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources.
The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits.
The National Institutes of Health and the Arthritis Foundation.
IMPORTANCE: Slowing myopia progression could decrease the risk of sight-threatening complications. OBJECTIVE: To determine whether soft multifocal contact lenses slow myopia progression in children, ...and whether high add power (+2.50 D) slows myopia progression more than medium (+1.50 D) add power lenses. DESIGN, SETTING, AND PARTICIPANTS: A double-masked randomized clinical trial that took place at 2 optometry schools located in Columbus, Ohio, and Houston, Texas. A total of 294 consecutive eligible children aged 7 to 11 years with −0.75 D to −5.00 D of spherical component myopia and less than 1.00 D astigmatism were enrolled between September 22, 2014, and June 20, 2016. Follow-up was completed June 24, 2019. INTERVENTIONS: Participants were randomly assigned to wear high add power (n = 98), medium add power (n = 98), or single-vision (n = 98) contact lenses. MAIN OUTCOMES AND MEASURES: The primary outcome was the 3-year change in cycloplegic spherical equivalent autorefraction, as measured by the mean of 10 autorefraction readings. There were 11 secondary end points, 4 of which were analyzed for this study, including 3-year eye growth. RESULTS: Among 294 randomized participants, 292 (99%) were included in the analyses (mean SD age, 10.3 1.2 years; 177 60.2% were female; mean SD spherical equivalent refractive error, −2.39 1.00 D). Adjusted 3-year myopia progression was −0.60 D for high add power, −0.89 D for medium add power, and −1.05 D for single-vision contact lenses. The difference in progression was 0.46 D (95% CI, 0.29-0.63) for high add power vs single vision, 0.30 D (95% CI, 0.13-0.47) for high add vs medium add power, and 0.16 D (95% CI, −0.01 to 0.33) for medium add power vs single vision. Of the 4 secondary end points, there were no statistically significant differences between the groups for 3 of the end points. Adjusted mean eye growth was 0.42 mm for high add power, 0.58 mm for medium add power, and 0.66 mm for single vision. The difference in eye growth was −0.23 mm (95% CI, −0.30 to −0.17) for high add power vs single vision, −0.16 mm (95% CI, −0.23 to −0.09) for high add vs medium add power, and −0.07 mm (95% CI, −0.14 to −0.01) for medium add power vs single vision. CONCLUSIONS AND RELEVANCE: Among children with myopia, treatment with high add power multifocal contact lenses significantly reduced the rate of myopia progression over 3 years compared with medium add power multifocal and single-vision contact lenses. However, further research is needed to understand the clinical importance of the observed differences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02255474
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