Do seasonal-to-decadal climate predictions underestimate the predictability of the real world?

Seasonal-to-decadal predictions are inevitably uncertain, depending on the size of the predictable signal relative to unpredictable chaos. Uncertainties can be accounted for using ensemble techniques, permitting quantitative probabilistic forecasts. In a perfect system, each ensemble member would represent a potential realization of the true evolution of the climate system, and the predictable components in models and reality would be equal. However, we show that the predictable component is sometimes lower in models than observations, especially for seasonal forecasts of the North Atlantic Oscillation and multiyear forecasts of North Atlantic temperature and pressure. In these cases the forecasts are underconfident, with each ensemble member containing too much noise. Consequently, most deterministic and probabilistic measures underestimate potential skill and idealized model experiments underestimate predictability. However, skilful and reliable predictions may be achieved using a large ensemble to reduce noise and adjusting the forecast variance through a postprocessing technique proposed here.

Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment.

The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor-infiltrating T cells (TILs), hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. We reveal that the solid TME imposes perpetual acetyl-coenzyme A (CoA) carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, which sustains cancer control.

Spatiotemporal mapping of immune and stem cell dysregulation after volumetric muscle loss.

Volumetric muscle loss (VML) is an acute trauma that results in persistent inflammation, supplantation of muscle tissue with fibrotic scarring, and decreased muscle function. The cell types, nature of cellular communication, and tissue locations that drive the aberrant VML response have remained elusive. Herein, we used spatial transcriptomics on a mouse model of VML and observed that VML engenders a unique spatial profibrotic pattern driven by crosstalk between fibrotic and inflammatory macrophages and mesenchymal-derived cells. The dysregulated response impinged on muscle stem cell-mediated repair, and targeting this circuit resulted in increased regeneration and reductions in inflammation and fibrosis. Collectively, these results enhance our understanding of the cellular crosstalk that drives aberrant regeneration and provides further insight into possible avenues for fibrotic therapy exploration.

Maresin 1 repletion improves muscle regeneration after volumetric muscle loss.

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied, and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.

Arabidopsis T-DNA insertional lines for CDC25 are hypersensitive to hydroxyurea but not to zeocin or salt stress.

BACKGROUND AND AIMS: In yeasts and animals, cyclin-dependent kinases are key regulators of cell cycle progression and are negatively and positively regulated by WEE1 kinase and CDC25 phosphatase, respectively. In higher plants a full-length orthologue of CDC25 has not been isolated but a shorter gene with homology only to the C-terminal catalytic domain is present. The Arabidopis thaliana;CDC25 can act as a phosphatase in vitro. Since in arabidopsis, WEE1 plays an important role in the DNA damage/DNA replication checkpoints, the role of Arath;CDC25 in conditions that induce these checkpoints or induce abiotic stress was tested. Methods arath;cdc25 T-DNA insertion lines, Arath;CDC25 over-expressing lines and wild type were challenged with hydroxyurea (HU) and zeocin, substances that stall DNA replication and damage DNA, respectively, together with an abiotic stressor, NaCl. A molecular and phenotypic assessment was made of all genotypes Key RESULTS: There was a null phenotypic response to perturbation of Arath;CDC25 expression under control conditions. However, compared with wild type, the arath;cdc25 T-DNA insertion lines were hypersensitive to HU, whereas the Arath;CDC25 over-expressing lines were relatively insensitive. In particular, the over-expressing lines consistently outgrew the T-DNA insertion lines and wild type when challenged with HU. All genotypes were equally sensitive to zeocin and NaCl. CONCLUSIONS: Arath;CDC25 plays a role in overcoming stress imposed by HU, an agent know to induce the DNA replication checkpoint in arabidopsis. However, it could not enhance tolerance to either a zeocin treatment, known to induce DNA damage, or salinity stress.

Supercritical carbon dioxide decellularization of plant material to generate 3D biocompatible scaffolds.

The use of plant-based biomaterials for tissue engineering has recently generated interest as plant decellularization produces biocompatible scaffolds which can be repopulated with human cells. The predominant approach for vegetal decellularization remains serial chemical processing. However, this technique is time-consuming and requires harsh compounds which damage the resulting scaffolds. The current study presents an alternative solution using supercritical carbon dioxide (scCO2). Protocols testing various solvents were assessed and results found that scCO2 in combination with 2% peracetic acid decellularized plant material in less than 4 h, while preserving plant microarchitecture and branching vascular network. The biophysical and biochemical cues of the scCO2 decellularized spinach leaf scaffolds were then compared to chemically generated scaffolds. Data showed that the scaffolds had a similar Young's modulus, suggesting identical stiffness, and revealed that they contained the same elements, yet displayed disparate biochemical signatures as assessed by Fourier-transform infrared spectroscopy (FTIR). Finally, human fibroblast cells seeded on the spinach leaf surface were attached and alive after 14 days, demonstrating the biocompatibility of the scCO2 decellularized scaffolds. Thus, scCO2 was found to be an efficient method for plant material decellularization, scaffold structure preservation and recellularization with human cells, while performed in less time (36 h) than the standard chemical approach (170 h).

Detection of adulteration in Hydrastis canadensis (goldenseal) dietary supplements via untargeted mass spectrometry-based metabolomics.

Current estimates report that approximately 25% of U.S. adults use dietary supplements for medicinal purposes. Yet, regulation and transparency within the dietary supplement industry remains a challenge, and economic incentives encourage adulteration or augmentation of botanical dietary supplement products. Undisclosed changes to the dietary supplement composition could impact safety and efficacy; thus, there is a continued need to monitor possible botanical adulteration or mis-identification. Goldenseal, Hydrastis canadensis L. (Ranunculaceae), is a well-known botanical used to combat bacterial infections and digestive problems and is widely available as a dietary supplement. The goal of this study was to evaluate potential adulteration in commercial botanical products using untargeted metabolomics, with H. canadensis supplements serving as a test case. An untargeted ultraperformance liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis was performed on 35 H. canadensis commercial products. Visual inspection of the chemometric data via principal component analysis (PCA) revealed several products that were distinct from the main groupings of samples, and subsequent evaluation of contributing metabolites led to their confirmation of the outliers as originating from a non-goldenseal species or a mixture of plant materials. The obtained results demonstrate the potential for untargeted metabolomics to discriminate between multiple unknown products and predict possible adulteration.

Conventional and accelerated-solvent extractions of green tea (camellia sinensis) for metabolomics-based chemometrics.

Metabolomics has emerged as an important analytical technique for multiple applications. The value of information obtained from metabolomics analysis depends on the degree to which the entire metabolome is present and the reliability of sample treatment to ensure reproducibility across the study. The purpose of this study was to compare methods of preparing complex botanical extract samples prior to metabolomics profiling. Two extraction methodologies, accelerated solvent extraction and a conventional solvent maceration, were compared using commercial green tea [Camellia sinensis (L.) Kuntze (Theaceae)] products as a test case. The accelerated solvent protocol was first evaluated to ascertain critical factors influencing extraction using a D-optimal experimental design study. The accelerated solvent and conventional extraction methods yielded similar metabolite profiles for the green tea samples studied. The accelerated solvent extraction yielded higher total amounts of extracted catechins, was more reproducible, and required less active bench time to prepare the samples. This study demonstrates the effectiveness of accelerated solvent as an efficient methodology for metabolomics studies.

Pharmacist-only trimethoprim: pharmacist satisfaction on their training and the impact on their practice.

Background In 2012, in a first for the developed world, New Zealand reclassified trimethoprim to allow specially trained pharmacists to supply the medicine without a prescription to women with cystitis fitting specific criteria. Objective This study explored pharmacists' views of the training and screening tool, impact on practice, and the pharmacists' perceptions of views of patients and doctors. Methods Structured interviews were conducted with 28 New Zealand pharmacists trained to supply trimethoprim. These pharmacists were selected to represent geographical spread as well as urban, suburban and rural. The key areas for investigation were: satisfaction about training, appropriateness of training, opinions on the screening tool, impact on clinical practice and perception of others. Audio recorded interviews were thematically analyzed. Results Of 40 pharmacies invited, 28 pharmacists agreed to participate. Most pharmacists were positive about being able to supply trimethoprim, the training and increased clinical focus of their practice. The content of the training was considered appropriate, as was the screening tool, which was well utilised during consultations. Minor suggestions on the training and consultation materials were provided. Some pharmacists reported that referral to the doctor without supply in a minority of trimethoprim consultations, frustrated some women. Frequency of supplies varied considerably by pharmacists from none supplied to weekly supplies. Some pharmacists questioned the exclusion to supply for women who had taken antibiotics in the last six months. Many women had reportedly appreciated the easier access in the pharmacy compared with doctor access, especially at weekends, but sometimes misunderstood the role of the pharmacist in the supply. While pharmacists reported that some doctors had been negative about pharmacist-supply, others were informing women about the service from the pharmacist. Conclusion Pharmacist supply of trimethoprim using mandated training and a screening tool or algorithm for supply is workable and well-accepted by pharmacists. Minor changes have been recommended. Further research is needed to understand perspectives of other stakeholders (women, doctors and practice nurses) and outcomes for patients.