New technologies are made possible by public and private R&D. Investments in education increase skills for decision making—denoted as allocative efficiency. In an environment with dynamic technology, ...farmers with more education are better able to make technology adoption decisions in a dynamic economic and technical environment. Societies have developed institutions and policies for sharing the costs of education and obtaining the benefits.
Single-molecule long-read DNA sequencing with biological nanopores is fast and high-throughput but suffers reduced accuracy in homonucleotide stretches. We now combine the CsgG nanopore with the ...35-residue N-terminal region of its extracellular interaction partner CsgF to produce a dual-constriction pore with improved signal and base-calling accuracy for homopolymer regions. The electron cryo-microscopy structure of CsgG in complex with full-length CsgF shows that the 33 N-terminal residues of CsgF bind inside the β-barrel of the pore, forming a defined second constriction. In complexes of CsgG bound to a 35-residue CsgF constriction peptide, the second constriction is separated from the primary constriction by ~25 Å. We find that both constrictions contribute to electrical signal modulation during single-stranded DNA translocation. DNA sequencing using a prototype CsgG-CsgF protein pore with two constrictions improved single-read accuracy by 25 to 70% in homopolymers up to 9 nucleotides long.
Vague food labels and distorted product claims have persisted in the “natural” food industry, while organic claims can be certified by the U.S. Department of Agriculture (USDA). Using experimental ...methods and a sample of randomly selected subjects, we test food label and information treatment effects on subjects' willingness-to-pay (WTP) for organic, “natural,” and conventional foods. Random nth-price auctions are used to elicit WTP after subjects received one of five randomly assigned information treatments. We find large information effects, including asymmetric cross-market effects for natural and organic foods. Perhaps surprising is that organic premiums increase in response to subjects seeing the “natural” foods industry's perspective on its products. Demographics effects are also important. The results have practical implications for natural and organic food marketing and valuing products where there are vague claims about their attributes.
Autophagy is an essential cellular degradation pathway in neurons; defects in autophagy are sufficient to induce neurodegeneration. In this paper, we investigate autophagosome dynamics in primary ...dorsal root ganglion neurons. Autophagosome biogenesis occurs distally in a constitutive process at the neurite tip. Autophagosomes initially move bidirectionally and then switch to unidirectional, processive movement toward the cell soma driven by dynein. Autophagosomes copurify with anterograde and retrograde motors, suggesting that the activity of bound kinesin motors is effectively down-regulated to yield robust retrograde motility driven by dynein. Both organelle and soluble cargoes are internalized into autophagosomes, including mitochondria and ubiquitin. As autophagosomes move distally to proximally, they undergo maturation and become increasingly acidified, consistent with the formation of an autolysosomal compartment that may more efficiently degrade cargo. This maturation is accompanied by a switch to bidirectional motility characteristic of lysosomes. Together, autophagosome biogenesis and maturation in primary neurons is a constitutive process that is spatially and temporally regulated along the axon.
Until recently, long‐range forecast systems showed only modest levels of skill in predicting surface winter climate around the Atlantic Basin and associated fluctuations in the North Atlantic ...Oscillation at seasonal lead times. Here we use a new forecast system to assess seasonal predictability of winter North Atlantic climate. We demonstrate that key aspects of European and North American winter climate and the surface North Atlantic Oscillation are highly predictable months ahead. We demonstrate high levels of prediction skill in retrospective forecasts of the surface North Atlantic Oscillation, winter storminess, near‐surface temperature, and wind speed, all of which have high value for planning and adaptation to extreme winter conditions. Analysis of forecast ensembles suggests that while useful levels of seasonal forecast skill have now been achieved, key sources of predictability are still only partially represented and there is further untapped predictability.
Key Points
The winter NAO can be skilfully predicted months ahead
The signal‐to‐noise ratio of the predictable signal is anomalously low
Predictions of the risk of regional winter extremes are possible
Summary Background Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor ...with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. Methods In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40–240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1–21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg in one cohort to 25 mg in all other cohorts once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov , number NCT01583283. Findings Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1–21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1–2 in 14 37% patients; grade 3 in seven 18%) and diarrhoea (grade 1–2 in 15 39% patients; grade 3 in two 5%). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% 95% CI 38–71) of 38 patients had an overall response. Interpretation The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. Funding Acetylon Pharmaceuticals.
We examined potential synergistic effects of racial and socioeconomic inequality associated with small-for-gestational-age (SGA) birth.
Electronic medical records from singleton births to White and ...Black women in 10 US states and the District of Columbia (n = 121 758) were linked to state-level indicators of structural racism, including the ratios of Blacks to Whites who were employed, were incarcerated, and had a bachelor's or higher degree. We used state-level Gini coefficients to assess income inequality. Generalized estimating equations models were used to quantify the adjusted odds of SGA birth associated with each indicator and the joint effects of structural racism and income inequality.
Structural racism indicators were associated with higher odds of SGA birth, and similar effects were observed for both races. The joint effects of racial and income inequality were significantly associated with SGA birth only when levels of both were high; in areas with high inequality levels, adjusted odds ratios ranged from 1.81 to 2.11 for the 3 structural racism indicators.
High levels of racial inequality and socioeconomic inequality appear to increase the risk of SGA birth, particularly when they co-occur.
Sustainable aviation fuels (SAFs) are expected to play an essential role in achieving the aviation industries' goal of carbon-neutral growth. However, producing biomass-based SAFs may induce changes ...in global land use and the associated carbon stock. The induced land use change (ILUC) emissions, as a part of the full life-cycle emissions for SAF pathways, will affect whether and to what extent SAFs reduce emissions compared with petroleum-based jet fuels. Here, we estimate the ILUC emission intensity for seventeen SAF pathways considered by the International Civil Aviation Organization (ICAO), covering five ASTM-certified technologies, nine biomass-based feedstocks, and four geographical regions. We introduce the SAF pathways into a well-established computable general equilibrium (CGE) model, GTAP-BIO, and its coupled emission accounting model, AEZ-EF, to study economy-wide implications of SAF production and estimate ILUC emissions intensity for each pathway. The estimated SAF ILUC emission intensities, using a 25-year amortization period, range from −58.5 g CO2e MJ−1 for the USA miscanthus alcohol (isobutanol)-to-jet (ATJ) pathway to 34.6 g CO2e MJ−1 for the Malaysia & Indonesia palm oil Hydrotreated Esters of Fatty Acids (HEFA) pathway. Notably, the vegetable oil pathways tend to have higher ILUC emission intensities due to their linkage to palm expansion and peatland oxidation in Southeast Asia. The cellulosic pathways studied provide negative ILUC emissions, mainly driven by the high carbon sequestrations in crop biomass and soil. Using the core life-cycle emissions established by ICAO, we show that fifteen of the assessed pathways have a lower full life-cycle emission intensity than petroleum-based jet fuels (89 g CO2e MJ−1), offering promising options to reduce aviation emissions.
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•The use of biojet fuels could contribute to aviation emission reductions.•Biojet induced land use change (ILUC) emissions play a key role in the life-cycle.•We estimate ILUC emission intensities for 17 biojet pathways using a CGE model.•The estimated ILUC emission intensities ranging from −58.5 to 34.6 g CO2e MJ−1.•Most (15) pathways resulted in lower life-cycle emissions than petroleum fuels.
Oncologists are at high risk of poor mental health. Prior research has focused on burnout, and has identified heavy workload as a key predictor. Compassion fatigue among physicians has generally ...received less attention, although medical specialties such as oncology may be especially at risk of compassion fatigue. We contribute to research by identifying predictors of both burnout and compassion fatigue among oncologists. In doing so, we distinguish between quantitative workload (e.g., work hours) and subjective work pressure, and test whether work-family conflict mediates the relationships between work pressure and burnout or compassion fatigue.
In a cross-sectional study, oncologists from across Canada (n = 312) completed questionnaires assessing burnout, compassion fatigue, workload, time pressure at work, work-family conflict, and other personal, family, and occupational characteristics. Analyses use Ordinary Least Squares regression.
Subjective time pressure at work is a key predictor of both burnout and compassion fatigue. Our results also show that work-family conflict fully mediates these relationships. Overall, the models explain more of the variation in burnout as compared to compassion fatigue.
Our study highlights the need to consider oncologists' subjective time pressure, in addition to quantitative workload, in interventions to improve mental health. The findings also highlight a need to better understand additional predictors of compassion fatigue.
•Studies examining DTI findings and cognition following TBI were meta-analysed.•Better cognitive functioning was related to DTI findings from many brain regions.•Memory and attention were most ...strongly associated with DTI findings.
Cognitive impairments are common following a traumatic brain injury (TBI) and frequently result from white matter (WM) damage. This damage can be quantified using diffusion tensor imaging (DTI), which measures the directionality (fractional anisotropy: FA) and amount (mean diffusivity/apparent diffusion coefficient: MD/ADC) of water diffusion in WM, with high FA and low MD/ADC thought to indicate greater WM integrity. However, the relationship between DTI and cognitive outcomes is currently unclear. The data from 20 studies that examined the relationship between WM integrity (measured using DTI) and cognition (categorised into seven domains) following mild-severe adult TBI were meta-analysed. Overall, high FA and low MD/ADC in most brain regions was associated with better cognitive performance, with memory and attention most strongly related to DTI findings. Specifically, memory and/or attention were very strongly related to DTI findings in the corpus callosum, fornix, internal capsule, arcuate and uncinate fasciculi. However, most findings were based on single studies and therefore await replication. Larger-scale, longitudinal studies are now needed to determine the predictive utility of DTI.
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