Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Influences of phosphorus-modified biochar on bacterial community and diversity in rhizosphere soil.

Root-associated bacteria play a vital role in the soil ecosystem and plant productivity. Previous studies have reported the decline of bacterial community and rhizosphere soil quality in the cultivation of some medicinal plants (i.e., Pseudostellaria heterophylla). Phosphorus (P)-modified biochar has the potential to improve soil health and quality. However, its influence on the bacterial community and diversity in the rhizosphere of medicinal plants is not well understood. Therefore, this study aims to investigate the effects of P-modified biochar on the bacterial community and diversity in the rhizosphere of P. heterophylla. Soil samples were collected from the rhizosphere of 4-month P. heterophylla under control (no biochar), 3% unmodified and 3% P-modified biochar treatments, respectively. Compared with control and unmodified biochar treatment, P-modified biochar significantly increased the relative abundance of plant-beneficial bacteria (P < 0.05), particularly Firmicutes, Nitrospirae and Acidobacteria. The relative abundance of Bacillus, belonging to Firmicutes, was dramatically raised from 0.032% in control group to 1.723% in P-modified biochar-treated group (P < 0.05). These results indicate the potential enhancement of soil quality for the growth of medicinal plants. The application of biochar significantly increased bacterial richness and bacterial diversity (P < 0.05). P modification of biochar did not have significant effects on soil bacterial richness (P > 0.05), while it reduced Shannon and increased Simpson diversity index of soil bacterial communities significantly (P < 0.05). It indicates a decrease in bacterial diversity. This research provides a new perspective for understanding the role of P-modified biochar in the rhizosphere ecosystem.

Advancing freshwater ecological forecasts: Harmful algal blooms in Lake Erie.

Ecological models help provide forecasts of ecosystem responses to natural and anthropogenic stresses. However, their ability to create reliable predictions requires forecasts with track records sufficiently long to build confidence, skill assessments, and treating uncertainty quantitatively. We use Lake Erie harmful algal blooms as a case study to help formalize ecological forecasting. Key challenges for models include uncertainty in the deterministic structure of the load-bloom relationship and the need to assess alternative drivers (e.g., biologically available phosphorus load, spring load, longer term cumulative load) with a larger dataset. We enhanced a Bayesian model considering new information and an expanded data set, test it through cross validation and blind forecasts, quantify and discuss its uncertainties, and apply it for assessing historical and future scenarios. Allowing a segmented relationship between bloom size and spring load indicates that loading above 0.15 Gg/month will have a substantially higher marginal impact on bloom size. The new model explains 84 % of interannual variability (9.09 Gg RMSE) when calibrated to the 19-year data set and 66 % of variability in cross validation (12.58 Gg RMSE). Blind forecasts explain 84 % of HAB variability between 2014 and 2020, which is substantially better than the actual forecast track record (R2 = 0.32) over this same period. Because of internal phosphorus recycling, represented by the long-term cumulative load, it could take over a decade for HABs to fully respond to loading reductions, depending on the pace of those reductions. Thus, the desired speed and endpoint of the lake's recovery should be considered when updating and adaptively managing load reduction targets. Results are discussed in the context of ecological forecasting best pactices: incorporate new knowledge and data in model construction; account for multiple sources of uncertainty; evaluate predictive skill through validation and hindcasting; and answer management questions related to both short-term forecasts and long-term scenarios.

Benefits of Tai Chi Quan on neurodegenerative diseases: A systematic review.

BACKGROUND: Neurodegenerative diseases have become an important concern with the accelerated aging process. Tai Chi Quan (TCQ) has positive benefits for brain health and chronic diseases. The aim of this study was to summarize the protective effects of TCQ for motor function, cognition, quality of life, and mood in patients with neurodegenerative diseases. METHODS: A systematic search was conducted via PubMed database and the Web of Science core collection database until August 20, 2021. The available English systematic reviews, meta-analyses, and clinical trials were included. Two reviewers completed the screening and assessment process independently. RESULTS: A total of 28 studies on Parkinson's disease, 21 on cognitive impairment, and 9 on multiple sclerosis met the included criteria. The study found that TCQ remarkably improved general motor function and balance, and prevented falls for Parkinson's disease. TCQ significantly improved global cognitive function for cognitive impairment. TCQ was likely safe and beneficial for multiple sclerosis as result of heterogeneous outcomes and small samples. CONCLUSION: TCQ exercise can effectively improve the motor function, global cognitive function, and falls in patients with neurodegenerative diseases. However, the positive effects of TCQ on the quality of life and mood of patients with neurodegenerative diseases need further evidence.

Wind-Driven Sediment Resuspension in the World's Fourth Largest Lake Contributes Substantial Phosphorus Load to the 11th Largest Lake.

Capturing precipitation-based episodes is a longstanding issue for estimating tributary loads; however, wind-driven resuspension in Lake Huron creates similar uncertainties in its estimated load to Lake Erie. Recent suggestions that the phosphorus load from Lake Huron is underestimated because sampling frequencies miss contributions from resuspension events are speculative because they did not include direct load measurements, address all resuspension regions, or assess the potential bioavailability of the load. We address these shortcomings by evaluating Lake Huron's nearshore regions, characterizing the biological availability of the load, and providing direct comparisons of load estimates with and without the resuspended load. We show that total phosphorus concentrations in Lake Huron and the St. Clair River are higher during resuspension events and that bioavailability of that material is comparable to that reported elsewhere. New load estimates, based on continuous turbidity measurements converted to phosphorus through P-turbidity relationships, were almost 90% higher than traditional load estimates, providing empirical evidence for the significantly underestimated previous load. This confirmation is important because if the Lake Huron load is not decreased, reductions from other sources would be needed to meet the overall reduction targets set by the binational Great Lakes Water Quality Agreement.

Effects of phosphorus-modified biochar as a soil amendment on the growth and quality of Pseudostellaria heterophylla.

Phosphorus (P) deficiency in agricultural soil is a worldwide concern. P modification of biochar, a common soil conditioner produced by pyrolysis of wastes and residues, can increase P availability and improve soil quality. This study aims to investigate the effects of P-modified biochar as a soil amendment on the growth and quality of a medicinal plant (Pseudostellaria heterophylla). P. heterophylla were grown for 4 months in lateritic soil amended with P-modified and unmodified biochar (peanut shell) at dosages of 0, 3% and 5% (by mass). Compared with unmodified biochar, P-modified biochar reduced available heavy metal Cd in soil by up to 73.0% and osmotic suction in the root zone by up to 49.3%. P-modified biochar application at 3% and 5% promoted the tuber yield of P. heterophylla significantly by 68.6% and 136.0% respectively. This was different from that in unmodified biochar treatment, where tuber yield was stimulated at 3% dosage but inhibited at 5% dosage. The concentrations of active ingredients (i.e., polysaccharides, saponins) in tuber were increased by 2.9-78.8% under P-modified biochar amendment compared with control, indicating the better tuber quality. This study recommended the application of 5% P-modified biochar for promoting the yield and quality of P. heterophylla.

[Application and significance of mixed methods research in traditional Chinese medicine and narrative medicine].

Since narrative medicine was introduced in China, it has been widely used in medical education and clinical practice. The research on narrative medicine in China is especially characterized by its combination with traditional Chinese medicine(TCM). At present, the research on narrative medicine in China is still in the stage of small-scale practicing and theory advocating. Besides, there is also a lack of guidance on experimental design methodology for clinical application, which leads to few high-quality studies in this field. The present study reviewed the current high-quality research on narrative medicine to discuss the value and prospects of mixed methods research in narrative medicine. In addition, the common design, application procedures, and notes of mixed methods research were explained to provide references for the extensive applications of narrative medicine in the medical field, especially TCM clinical practice, education, and scientific research.

Quality and yield of Pseudostellaria heterophylla treated with GGBS as pH adjuster against the toxicity of Cd and Cu.

The contamination of Cd and Cu in soil is a great threat to medicinal plant. Ground granulated blast furnace slag (GGBS) is a potential soil pH adjuster to reduce metal toxicity. However, how GGBS affects the quality and yield of herbal plants under the stress of Cd and Cu is not clear. This study aims to investigate the quality and yield of a medicinal plant (Pseudostellaria heterophylla) responding to GGBS treatment in Cd and Cu contaminated soil. GGBS with three mass percentages (0%, 3%, 5%) was added into contaminated lateritic soils for planting. Each condition had 21 replicated seedlings. The concentrations of Cd and Cu in plant, amounts of active ingredients (polysaccarides and saponins) in medicinal organ, and tuber properties were measured after harvest. The results showed that under 3% and 5% GGBS treatments, Cd and Cu accumulations in all plant organs (leaf, stem, root and tuber) were reduced by 69.4-86.0% and 10.3-30.1%, respectively. They were below the permissible limits (World Health Organization, WHO). Even though the concentrations of active ingredients in P. heterophylla tuber decreased by up to 35.8%, they still met Hong Kong Chinese Materia Medica standard. Besides, the biomass of root tuber increased by 9.8% and 46%, due to 3% and 5% GGBS treatments, respectively. The recommended 5% GGBS treatment in practice can balance the reduction of active ingredients and the increase of plant yield when minimizing Cd and Cu accumulation in tuber.

Uncertainty in critical source area predictions from watershed-scale hydrologic models.

Watershed-scale hydrologic models are frequently used to inform conservation and restoration efforts by identifying critical source areas (CSAs; alternatively 'hotspots'), defined as areas that export relatively greater quantities of nutrients and sediment. The CSAs can then be prioritized or 'targeted' for conservation and restoration to ensure efficient use of limited resources. However, CSA simulations from watershed-scale hydrologic models may be uncertain and it is critical that the extent and implications of this uncertainty be conveyed to stakeholders and decision makers. We used an ensemble of four independently developed Soil and Water Assessment Tool (SWAT) models and a SPAtially Referenced Regression On Watershed attributes (SPARROW) model to simulate CSA locations for flow, phosphorus, nitrogen, and sediment within the ~17,000-km2 Maumee River watershed at the HUC-12 scale. We then assessed uncertainty in CSA simulations determined as the variation in CSA locations across the models. Our application of an ensemble of models - differing with respect to inputs, structure, and parameterization - facilitated an improved accounting of CSA prediction uncertainty. We found that the models agreed on the location of a subset of CSAs, and that these locations may be targeted with relative confidence. However, models more often disagreed on CSA locations. On average, only 16%-46% of HUC-12 subwatersheds simulated as a CSA by one model were also simulated as a CSA by a different model. Our work shows that simulated CSA locations are highly uncertain and may vary substantially across models. Hence, while models may be useful in informing conservation and restoration planning, their application to identify CSA locations would benefit from comprehensive uncertainty analyses to avoid inefficient use of limited resources.

Evaluating management options to reduce Lake Erie algal blooms using an ensemble of watershed models.

Reducing harmful algal blooms in Lake Erie, situated between the United States and Canada, requires implementing best management practices to decrease nutrient loading from upstream sources. Bi-national water quality targets have been set for total and dissolved phosphorus loads, with the ultimate goal of reaching these targets in 9-out-of-10 years. Row crop agriculture dominates the land use in the Western Lake Erie Basin thus requiring efforts to mitigate nutrient loads from agricultural systems. To determine the types and extent of agricultural management practices needed to reach the water quality goals, we used five independently developed Soil and Water Assessment Tool models to evaluate the effects of 18 management scenarios over a 10-year period on nutrient export. Guidance from a stakeholder group was provided throughout the project, and resulted in improved data, development of realistic scenarios, and expanded outreach. Subsurface placement of phosphorus fertilizers, cover crops, riparian buffers, and wetlands were among the most effective management options. But, only in one realistic scenario did a majority (3/5) of the models predict that the total phosphorus loading target would be met in 9-out-of-10 years. Further, the dissolved phosphorus loading target was predicted to meet the 9-out-of-10-year goal by only one model and only in three scenarios. In all scenarios evaluated, the 9-out-of-10-year goal was not met based on the average of model predictions. Ensemble modeling revealed general agreement about the effects of several practices although some scenarios resulted in a wide range of uncertainty. Overall, our results demonstrate that there are multiple pathways to approach the established water quality goals, but greater adoption rates of practices than those tested here will likely be needed to attain the management targets.

Quantifying uncertainty cascading from climate, watershed, and lake models in harmful algal bloom predictions.

In response to increased harmful algal blooms (HABs), hypoxia, and nearshore algae growth in Lake Erie, the United States and Canada agreed to phosphorus load reduction targets. While the load targets were guided by an ensemble of models, none of them considered the effects of climate change. Some watershed models developed to guide load reduction strategies have simulated climate effects, but without extending the resulting loads or their uncertainties to HAB projections. In this study, we integrated an ensemble of four climate models, three watershed models, and four HAB models. Nutrient loads and HAB predictions were generated for historical (1985-1999), current (2002-2017), and mid-21st-century (2051-2065) periods. For the current and historical periods, modeled loads and HABs are comparable to observations but exhibit less interannual variability. Our results show that climate impacts on watershed processes are likely to lead to reductions in future loading, assuming land use and watershed management practices are unchanged. This reduction in load should help reduce the magnitude of future HABs, although increases in lake temperature could mitigate that decrease. Using Monte-Carlo analysis to attribute sources of uncertainty from this cascade of models, we show that the uncertainty associated with each model is significant, and that improvements in all three are needed to build confidence in future projections.

Lake Huron's Phosphorus Contributions to the St. Clair-Detroit River Great Lakes Connecting Channel.

The United States and Canada called for a 40% load reduction of total phosphorus from 2008 levels entering the western and central basins of Lake Erie to achieve a 6000 MTA target and help reduce its central basin hypoxia. The Detroit River is a significant source of total phosphorus to Lake Erie; it in turn has been reported to receive up to 58% of its load from Lake Huron when accounting for resuspended sediment loads previously unmonitored at the lake outlet. Key open questions are where does this additional load originate, what drives its variability, and how often does it occur. We used a hydrodynamic model, satellite images of resuspension events and ice cover, wave hindcasts, and continuous turbidity measurements at the outlet of Lake Huron to determine where in Lake Huron the undetected load originates and what drives its variability. We show that the additional sediment load, and likely phosphorus, is from wave-induced Lake Huron sediment resuspension, primarily within 30 km of the southeastern shore. When the flow is from southwest or down the center of the lake, the resuspended sediment is not detected at Canada's sampling station at the head of the St. Clair River.

Creatine uptake regulates CD8 T cell antitumor immunity.

T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine supplementation with a PD-1/PD-L1 blockade treatment showed synergistic tumor suppression efficacy. We further demonstrated that creatine acts as a "molecular battery" conserving bioenergy to power T cell activities. Therefore, our results have identified creatine as an important metabolic regulator controlling antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell-based cancer immunotherapies.

Metabolomic analysis of raw Pinelliae Rhizoma and its alum-processed products via UPLC-MS and their cytotoxicity.

Alum-processing is a traditional method to attenuate the toxicity of Pinelliae Rhizoma (tubers of Pinellia ternate, PT). The present study aimed at investigating the chemical and cytotoxic changes during alum processing. Metabolomic profiles of raw and alum-processed PT were studied based on ultra-performance liquid chromatography coupled with Orbitrap mass spectrometry. More than 80 chemicals in positive MS mode and 40 chemicals in negative MS mode, such as organic acids, amino acids, glucosides and nucleosides, were identified after multivariate statistical analysis, including principal component analysis and orthogonal partial least-square discriminant analysis. Almost all of the identified chemical markers were significantly decreased ~10- to 100-fold after alum processing. Meanwhile, the correlations between the chemical markers were assimilated to a positive coefficient from disorderly distribution during the processing. Raw PT extracts could inhibit the proliferation of human carcinoma cells (HCT-116, HepG2, and A549) at the rate of 40.5, 24.8 and 31.6% more strongly than processed PT. It was concluded that the alum processing of PT could decrease the number of actively water-soluble principles at the same time as decreasing toxicity. Given the water-insoluble property of toxic calcium oxalate raphides in PT, we suggest that a more scientific processing method should be sought.

Expression Analysis of Up-Regulated Genes Responding to Plumbagin in Escherichia coli.

Plumbagin is found in many medicinal plants and has been reported to have antimicrobial activities. We examined the molecular responses of Escherichia coli to plumbagin by using a proteomic approach to search for bacterial genes up-regulated by the drug. The protein profile obtained was compared with that of E. coli without the plumbagin treatment. Subsequent analyses of the induced proteins by mass spectroscopy identified several up-regulated genes, including ygfZ, whose function has not been defined. Analyses of the 5'-flanking sequences indicate that most of these genes contain a marbox-like stretch, and several of them are categorized as members of the mar/sox regulon. Representatives of these genes were cloned into plasmids, and the marbox-like sequences were modified by site-directed mutagenesis. It was proven that mutations in these regions substantially repressed the level of proteins encoded by the downstream genes. Furthermore, plumbagin's early effect was demonstrated to robustly induce SoxS rather than MarA, an observation distinctly different from that seen with sodium salicylate.