The Atlantic Multidecadal Oscillation (AMO) is a major mode of climate variability with important societal impacts. Most previous explanations identify the driver of the AMO as the ocean circulation, ...specifically the Atlantic Meridional Overturning Circulation (AMOC). Here we show that the main features of the observed AMO are reproduced in models where the ocean heat transport is prescribed and thus cannot be the driver. Allowing the ocean circulation to interact with the atmosphere does not significantly alter the characteristics of the AMO in the current generation of climate models. These results suggest that the AMO is the response to stochastic forcing from the mid-latitude atmospheric circulation, with thermal coupling playing a role in the tropics. In this view, the AMOC and other ocean circulation changes would be largely a response to, not a cause of, the AMO.
Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the ...process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE
and RefSeq
launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref.
) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.
Electronic medical records are emerging as a major source of data for clinical and translational research studies, although phenotypes of interest need to be accurately defined first. This article ...provides an overview of how to develop a phenotype algorithm from electronic medical records, incorporating modern informatics and biostatistics methods.
Recently developed technologies have enabled multi-well measurement of O(2) consumption, facilitating the rate of mitochondrial research, particularly regarding the mechanism of action of drugs and ...proteins that modulate metabolism. Among these technologies, the Seahorse XF24 Analyzer was designed for use with intact cells attached in a monolayer to a multi-well tissue culture plate. In order to have a high throughput assay system in which both energy demand and substrate availability can be tightly controlled, we have developed a protocol to expand the application of the XF24 Analyzer to include isolated mitochondria. Acquisition of optimal rates requires assay conditions that are unexpectedly distinct from those of conventional polarography. The optimized conditions, derived from experiments with isolated mouse liver mitochondria, allow multi-well assessment of rates of respiration and proton production by mitochondria attached to the bottom of the XF assay plate, and require extremely small quantities of material (1-10 µg of mitochondrial protein per well). Sequential measurement of basal, State 3, State 4, and uncoupler-stimulated respiration can be made in each well through additions of reagents from the injection ports. We describe optimization and validation of this technique using isolated mouse liver and rat heart mitochondria, and apply the approach to discover that inclusion of phosphatase inhibitors in the preparation of the heart mitochondria results in a specific decrease in rates of Complex I-dependent respiration. We believe this new technique will be particularly useful for drug screening and for generating previously unobtainable respiratory data on small mitochondrial samples.
Metabolomic studies of body fluids show that immune‐mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased ...bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast‐like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset‐specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early‐stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.
Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic ...variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception.
Breakthrough technologies to measure cellular oxygen consumption and proton efflux are reigniting the study of cellular energetics by increasing the scope and pace with which discoveries are made. As ...we learn the variation in metabolism between cell types is large, it is helpful to continually provide additional perspectives and update our roadmap for data interpretation. In that spirit, this chapter provides the following for those conducting microplate-based oxygen consumption experiments: (i) a description of the standard parameters for measuring respiration in intact cells, (ii) a framework for data analysis and normalization, and (iii) examples of measuring respiration in permeabilized cells to follow up results observed with intact cells. Additionally, rate-based measurements of extracellular pH are increasingly used as a qualitative indicator of glycolytic flux. As a resource to help interpret these measurements, this chapter also provides a detailed accounting of proton production during glucose oxidation in the context of plate-based assays.
Increasing evidence indicates a link between obesity and cognitive impairment. Furthermore, there is limited literature regarding the effect of polyphenols, a plant derived compounds, on executive ...functioning in an overweight/obese population at-risk of cognitive impairment. The aim of the present systematic review and meta-analysis of randomized controlled trials is to examine the effect of polyphenol supplementation on executive functions in overweight and/or obese populations at risk of cognitive impairment.
A comprehensive literature search was conducted from inception to March 2023 using four electronic databases: PubMed/Medline, PsycInfo, Scopus and Cochrane trials library. Published primary research studies in English that compared the effect of polyphenols with placebo on executive function in overweight/obese adults were considered eligible for the meta-analysis. Jadad scale was used for the methodological quality rating of the included studies. Hedges g with 95% confidence intervals (CI) for endpoints were calculated using random effect model where applicable. Rosenthal's Fail-safe N, funnel plots, the Begg and Mazumdar's rank correlation test (Kendall's S statistic P-Q), Egger's linear regression test, and Duval and Tweedie's trim-and-fill test were identified for potential use as appropriate, to examine publication bias. Sensitivity analysis was conducted to examine the robustness of the results.
A total of 23 RCT studies involving N = 1,976 participants were included in the review. The results of the meta-analysis revealed a non-significant effect for polyphenol supplementation on executive function (g = 0.076, CI = -0.018 to 0.170). Observations from primary studies within the meta-analysis showed a potential positive effect of polyphenol supplementation in a younger population at-risk of cognitive impairment and it is recommended to investigate this further in future studies. Moreover, the variability of the tasks used to examine executive functions as well as the adequate reporting of supplement's phenolic composition is a limitation that future work should also consider.
We analyze the Atlantic multidecadal oscillation (AMO) in the preindustrial (PI) and historical (HIST) simulations from the Coupled Model Intercomparison Project Phase 5 (CMIP5) to assess the drivers ...of the observed AMO from 1865 to 2005. We draw 141 year samples from the 41 CMIP5 model's PI runs and compare the correlation and variance between the observed AMO and the simulated PI and HIST AMO. The correlation coefficients in 38 forced (HIST) models are above the 90% confidence level and explain up to 56% of the observed variance. The probability that any of the unforced (PI) models do as well is less than 3% in 31 models. Multidecadal variability is larger in 39 CMIP5 HIST simulations and in all HIST members of the Community Earth System Model Large Ensemble than their corresponding PI. We conclude that there is an essential role for external forcing in driving the observed AMO.
Key Points
The chance of an unforced PI run correlating as well with the observed AMO as the historical run is less than 3% in 31 out of 41 models
The unforced PI models simulate less AMO variance than their forced historical simulations
Models need external forcing to explain the magnitude, timing, and multidecadal frequency of the observed twentieth century AMO
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