Comprehensive evidence implies a higher social cost of CO2.

The social cost of carbon dioxide (SC-CO2) measures the monetized value of the damages to society caused by an incremental metric tonne of CO2 emissions and is a key metric informing climate policy. Used by governments and other decision-makers in benefit-cost analysis for over a decade, SC-CO2 estimates draw on climate science, economics, demography and other disciplines. However, a 2017 report by the US National Academies of Sciences, Engineering, and Medicine1 (NASEM) highlighted that current SC-CO2 estimates no longer reflect the latest research. The report provided a series of recommendations for improving the scientific basis, transparency and uncertainty characterization of SC-CO2 estimates. Here we show that improved probabilistic socioeconomic projections, climate models, damage functions, and discounting methods that collectively reflect theoretically consistent valuation of risk, substantially increase estimates of the SC-CO2. Our preferred mean SC-CO2 estimate is $185 per tonne of CO2 ($44-$413 per tCO2: 5%-95% range, 2020 US dollars) at a near-term risk-free discount rate of 2%, a value 3.6 times higher than the US government's current value of $51 per tCO2. Our estimates incorporate updated scientific understanding throughout all components of SC-CO2 estimation in the new open-source Greenhouse Gas Impact Value Estimator (GIVE) model, in a manner fully responsive to the near-term NASEM recommendations. Our higher SC-CO2 values, compared with estimates currently used in policy evaluation, substantially increase the estimated benefits of greenhouse gas mitigation and thereby increase the expected net benefits of more stringent climate policies.

Mortality Attributable to Long-Term Exposure to Ambient Fine Particulate Matter: Insights from the Epidemiologic Evidence for Understudied Locations.

Epidemiologic cohort studies have consistently demonstrated that long-term exposure to ambient fine particles (PM2.5) is associated with mortality. Nevertheless, extrapolating results to understudied locations may involve considerable uncertainty. To explore this issue, this review discusses the evidence for (i) the associated risk of mortality, (ii) the shape of the concentration-response function, (iii) a causal interpretation, and (iv) how the source mix/composition of PM2.5 and population characteristics may alter the effect. The accumulated evidence suggests the following: (i) In the United States, the change in all-cause mortality risk per µg/m3 is about 0.8%. (ii) The concentration-response function appears nonlinear. (iii) Causation is overwhelmingly supported. (iv) Fossil fuel combustion-related sources are likely more toxic than others, and age, race, and income may modify the effect. To illustrate the use of our findings in support of a risk assessment in an understudied setting, we consider Kuwait. However, given the complexity of this relationship and the heterogeneity in reported effects, it is unreasonable to think that, in such circumstances, point estimates can be meaningful. Consequently, quantitative probabilistic estimates, which cannot be derived objectively, become essential. Formally elicited expert judgment can provide such estimates, and this review provides the evidence to support an elicitation.

Ice sheet contributions to future sea-level rise from structured expert judgment.

Despite considerable advances in process understanding, numerical modeling, and the observational record of ice sheet contributions to global mean sea-level rise (SLR) since the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change, severe limitations remain in the predictive capability of ice sheet models. As a consequence, the potential contributions of ice sheets remain the largest source of uncertainty in projecting future SLR. Here, we report the findings of a structured expert judgement study, using unique techniques for modeling correlations between inter- and intra-ice sheet processes and their tail dependences. We find that since the AR5, expert uncertainty has grown, in particular because of uncertain ice dynamic effects. For a +2 °C temperature scenario consistent with the Paris Agreement, we obtain a median estimate of a 26 cm SLR contribution by 2100, with a 95th percentile value of 81 cm. For a +5 °C temperature scenario more consistent with unchecked emissions growth, the corresponding values are 51 and 178 cm, respectively. Inclusion of thermal expansion and glacier contributions results in a global total SLR estimate that exceeds 2 m at the 95th percentile. Our findings support the use of scenarios of 21st century global total SLR exceeding 2 m for planning purposes. Beyond 2100, uncertainty and projected SLR increase rapidly. The 95th percentile ice sheet contribution by 2200, for the +5 °C scenario, is 7.5 m as a result of instabilities coming into play in both West and East Antarctica. Introducing process correlations and tail dependences increases estimates by roughly 15%.

Vine Regression with Bayes Nets: A Critical Comparison with Traditional Approaches Based on a Case Study on the Effects of Breastfeeding on IQ.

Regular vines (R-vines) copulas build high dimensional joint densities from arbitrary one-dimensional margins and (conditional) bivariate copula densities. Vine densities enable the computation of all conditional distributions, though the calculations can be numerically intensive. Saturated continuous nonparametric Bayes nets (CNPBN) are regular vines. Computing regression functions from the vine copula density is termed vine regression. The epicycles of regression-including/excluding covariates, interactions, higher order terms, multicollinearity, model fit, transformations, heteroscedasticity, bias-are dispelled. One simply computes the regressions from the vine copula density. Only the question of finding an adequate vine copula remains. Vine regression is applied to a data set from the National Longitudinal Study of Youth relating breastfeeding to IQ. The expected effects of breastfeeding on IQ depend on IQ, on the baseline level of breastfeeding, on the duration of additional breastfeeding and on the values of other covariates. A child given two weeks breastfeeding can expect to increase his/her IQ by 1.5-2 IQ points by adding 10 weeks of breastfeeding, depending on values of other covariates. A child given two years breastfeeding can expect to gain from 0.48-0.65 IQ points from 10 additional weeks. Adding 10 weeks breastfeeding to each of the 3,179 children in this data set has a net present value $50,700,000 according to the Bayes net, compared to $29,000,000 according to the linear regression.

Carpal tunnel syndrome and Raynaud's phenomenon: a narrative review.

BACKGROUND: Raynaud's phenomenon (RP) is a recognized symptom associated with carpal tunnel syndrome (CTS) and is also the vascular manifestation of hand arm vibration syndrome (HAVS). The symptoms of HAVS and CTS are such that there is a significant possibility of misdiagnosis and an incorrect attribution of vascular and sensory symptoms. An understanding of the relationship between RP and CTS is essential when undertaking health surveillance of vibration-exposed workers presenting with combined vascular and sensory symptoms. AIMS: To clarify the relationship between CTS and Raynaud's phenomenon. METHODS: A systematic search was undertaken of studies that reviewed links between CTS and Raynaud's phenomenon (RP). RESULTS: A total of 4170 papers were identified, with 21 articles that were then reviewed in full, including 1 meta-analysis of 8 studies. Eighteen papers, not included in the meta-analysis, were found including 3 case control studies, 9 case reports, 2 prospective studies and 4 retrospective reviews. Papers were reviewed on the basis of the diagnostic criteria used for CTS and RP. Our review of the literature confirms a substantial body of evidence of a relationship between RP and CTS. CONCLUSIONS: It is recommended that assessment of vibration exposed individuals who report concurrent RP and separate sensory symptoms suggestive of, or compatible with CTS, should formally exclude CTS before attributing symptoms to HAVS.

Attribution of Illnesses Transmitted by Food and Water to Comprehensive Transmission Pathways Using Structured Expert Judgment, United States.

Illnesses transmitted by food and water cause a major disease burden in the United States despite advancements in food safety, water treatment, and sanitation. We report estimates from a structured expert judgment study using 48 experts who applied Cooke's classical model of the proportion of disease attributable to 5 major transmission pathways (foodborne, waterborne, person-to-person, animal contact, and environmental) and 6 subpathways (food handler-related, under foodborne; recreational, drinking, and nonrecreational/nondrinking, under waterborne; and presumed person-to-person-associated and presumed animal contact-associated, under environmental). Estimates for 33 pathogens were elicited, including bacteria such as Salmonella enterica, Campylobacter spp., Legionella spp., and Pseudomonas spp.; protozoa such as Acanthamoeba spp., Cyclospora cayetanensis, and Naegleria fowleri; and viruses such as norovirus, rotavirus, and hepatitis A virus. The results highlight the importance of multiple pathways in the transmission of the included pathogens and can be used to guide prioritization of public health interventions.

Deciphering the super relaxed state of human ß-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.

Mutations in ß-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human ß-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.

A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly.

A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.

Piperine's mitigation of obesity and diabetes can be explained by its up-regulation of the metabolic rate of resting muscle.

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a high-throughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The Kd was ∼2 µM. Piperine had little effect on the mechanics of either fully active or resting muscle fibers. Previous work has shown that piperine can mitigate both obesity and type 2 diabetes in rodent models of these conditions. We propose that the increase in resting muscle metabolism contributes to these positive effects. The results described here show that up-regulation of resting muscle metabolism could treat obesity and type 2 diabetes and that piperine would provide a useful lead compound for the development of these therapies.

Piperine, an alkaloid inhibiting the super-relaxed state of myosin, binds to the myosin regulatory light chain.

Piperine, an alkaloid from black pepper, was found to inhibit the super-relaxed state (SRX) of myosin in fast-twitch skeletal muscle fibers. In this work we report that the piperine molecule binds heavy meromyosin (HMM), whereas it does not interact with the regulatory light chain (RLC)-free subfragment-1 (S1) or with control proteins from the same muscle molecular machinery, G-actin and tropomyosin. To further narrow down the location of piperine binding, we studied interactions between piperine and a fragment of skeletal myosin consisting of the full-length RLC and a fragment of the heavy chain (HCF). The sequence of HCF was designed to bind RLC and to dimerize via formation of a stable coiled coil, thus producing a well-folded isolated fragment of the myosin neck. Both chains were co-expressed in Escherichia coli, the RLC/HCF complex was purified and tested for stability, composition and binding to piperine. RLC and HCF chains formed a stable heterotetrameric complex (RLC/HCF)2 which was found to bind piperine. The piperine molecule was also found to bind isolated RLC. Piperine binding to RLC in (RLC/HCF)2 altered the compactness of the complex, suggesting that the mechanism of SRX inhibition by piperine is based on changing conformation of the myosin.

Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes.

Cardiac myosin binding protein-C (cMyBP-C) is a structural and regulatory component of cardiac thick filaments. It is observed in electron micrographs as seven to nine transverse stripes in the central portion of each half of the A band. Its C-terminus binds tightly to the myosin rod and contributes to thick filament structure, while the N-terminus can bind both myosin S2 and actin, influencing their structure and function. Mutations in the MYBPC3 gene (encoding cMyBP-C) are commonly associated with hypertrophic cardiomyopathy (HCM). In cardiac cells there exists a population of myosin heads in the super-relaxed (SRX) state, which are bound to the thick filament core with a highly inhibited ATPase activity. This report examines the role cMyBP-C plays in regulating the population of the SRX state of cardiac myosin by using an assay that measures single ATP turnover of myosin. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. A smaller, non-significant decrease is observed when thoracic aortic constriction is used to induce cardiac hypertrophy in mutation negative mice. These results support the proposal that cMyBP-C stabilises the thick filament and that the loss of cMyBP-C results in an untethering of myosin heads. This results in an increased myosin ATP turnover, further consolidating the relationship between thick filament structure and the myosin ATPase.

Rating impacts in a multi-stressor world: a quantitative assessment of 50 stressors affecting the Great Lakes.

Ecosystems often experience multiple environmental stressors simultaneously that can differ widely in their pathways and strengths of impact. Differences in the relative impact of environmental stressors can guide restoration and management prioritization, but few studies have empirically assessed a comprehensive suite of stressors acting on a given ecosystem. To fill this gap in the Laurentian Great Lakes, where considerable restoration investments are currently underway, we used expert elicitation via a detailed online survey to develop ratings of the relative impacts of 50 potential stressors. Highlighting the multiplicity of stressors in this system, experts assessed all 50 stressors as having some impact on ecosystem condition, but ratings differed greatly among stressors. Individual stressors related to invasive and nuisance species (e.g., dreissenid mussels and ballast invasion risk) and climate change were assessed as having the greatest potential impacts. These results mark a shift away from the longstanding emphasis on nonpoint phosphorus and persistent bioaccumulative toxic substances in the Great Lakes. Differences in impact ratings among lakes and ecosystem zones were weak, and experts exhibited surprisingly high levels of agreement on the relative impacts of most stressors. Our results provide a basin-wide, quantitative summary of expert opinion on the present-day influence of all major Great Lakes stressors. The resulting ratings can facilitate prioritizing stressors to achieve management objectives in a given location, as well as providing a baseline for future stressor impact assessments in the Great Lakes and elsewhere.

Use of structured expert judgment to forecast invasions by bighead and silver carp in Lake Erie.

Identifying which nonindigenous species will become invasive and forecasting the damage they will cause is difficult and presents a significant problem for natural resource management. Often, the data or resources necessary for ecological risk assessment are incomplete or absent, leaving environmental decision makers ill equipped to effectively manage valuable natural resources. Structured expert judgment (SEJ) is a mathematical and performance-based method of eliciting, weighting, and aggregating expert judgments. In contrast to other methods of eliciting and aggregating expert judgments (where, for example, equal weights may be assigned to experts), SEJ weights each expert on the basis of his or her statistical accuracy and informativeness through performance measurement on a set of calibration variables. We used SEJ to forecast impacts of nonindigenous Asian carp (Hypophthalmichthys spp.) in Lake Erie, where it is believed not to be established. Experts quantified Asian carp biomass, production, and consumption and their impact on 4 fish species if Asian carp were to become established. According to experts, in Lake Erie Asian carp have the potential to achieve biomass levels that are similar to the sum of biomasses for several fishes that are harvested commercially or recreationally. However, the impact of Asian carp on the biomass of these fishes was estimated by experts to be small, relative to long term average biomasses, with little uncertainty. Impacts of Asian carp in tributaries and on recreational activities, water quality, or other species were not addressed. SEJ can be used to quantify key uncertainties of invasion biology and also provide a decision-support tool when the necessary information for natural resource management and policy is not available.

The chromatin remodeller ACF acts as a dimeric motor to space nucleosomes.

Evenly spaced nucleosomes directly correlate with condensed chromatin and gene silencing. The ATP-dependent chromatin assembly factor (ACF) forms such structures in vitro and is required for silencing in vivo. ACF generates and maintains nucleosome spacing by constantly moving a nucleosome towards the longer flanking DNA faster than the shorter flanking DNA. How the enzyme rapidly moves back and forth between both sides of a nucleosome to accomplish bidirectional movement is unknown. Here we show that nucleosome movement depends cooperatively on two ACF molecules, indicating that ACF functions as a dimer of ATPases. Further, the nucleotide state determines whether the dimer closely engages one or both sides of the nucleosome. Three-dimensional reconstruction by single-particle electron microscopy of the ATPase-nucleosome complex in an activated ATP state reveals a dimer architecture in which the two ATPases face each other. Our results indicate a model in which the two ATPases work in a coordinated manner, taking turns to engage either side of a nucleosome, thereby allowing processive bidirectional movement. This novel dimeric motor mechanism differs from that of dimeric motors such as kinesin and dimeric helicases that processively translocate unidirectionally and reflects the unique challenges faced by motors that move nucleosomes.

The aggregation of expert judgment: do good things come to those who weight?

This responds to an "evaluation" of the classical model for structured expert judgment by Bolger and Rowe in this issue. This response references extensive expert judgment performance data in the public domain which played no role in their evaluation.