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.

Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking.

Hazel leaf, a by-product of hazelnuts, is commonly used in traditional folk medicine in Portugal, Sweden, Iran and other regions for properties such as vascular protection, anti-bleeding, anti-edema, anti-infection, and pain relief. Based on our previous studies, the polyphenol extract from hazel leaf was identified and quantified via HPLC fingerprint. The contents of nine compounds including kaempferol, chlorogenic acid, myricetin, caffeic acid, p-coumaric acid, resveratrol, luteolin, gallic acid and ellagic acid in hazel leaf polyphenol extract (ZP) were preliminary calculated, among which kaempferol was the highest with 221.99 mg/g, followed by chlorogenic acid with 8.23 mg/g. The inhibition of ZP on α-glucosidase and xanthine oxidase activities was determined via the chemical method, and the inhibition on xanthine oxidase was better. Then, the effect of ZP on hyperuricemia zebrafish was investigated. It was found that ZP obviously reduced the levels of uric acid, xanthine oxidase, urea nitrogen and creatinine, and up-regulated the expression ofOAT1 and HPRT genes in hyperuricemia zebrafish. Finally, the targeted network pharmacological analysis and molecular docking of nine polyphenol compounds were performed to search for relevant mechanisms for alleviating hyperuricemia. These results will provide a valuable basis for the development and application of hazel leaf polyphenols as functional ingredients.

Chitosan oligosaccharide improves intestinal function by promoting intestinal development, alleviating intestinal inflammatory response, and enhancing antioxidant capacity in broilers aged d 1 to 14.

This study was conducted to investigate the effects of chitosan oligosaccharide (COS) supplementation on intestinal development and functions, inflammatory response, antioxidant capacity and the related signaling pathways in broilers aged d 1 to 14. A total of 240 one-day old male Arbor Acres broilers (40.47 ± 0.30 g) were randomly allotted to 4 groups, and each group consisted of 6 replicate pens with 10 broilers per replicate. Broilers fed a basal diet supplementation with COS at 0 (CON group), 200 (COS200 group), 400 (COS400 group), and 800 mg/kg (COS800 group) for 14 d, respectively. Broilers in the COS supplementation groups had no significant effects on growth performance. Compared to the CON group, dietary COS supplementation increased (P < 0.05) the relative weight of duodenum, jejunal lipase activity, duodenal and ileal villus surface area, and lower (P < 0.05) ileal amylase and alkaline phosphatase activity, and crypt depth. The expression level of duodenal glucose transporter 1 (GLUT1), Na+-glucose cotransporter 1 (SGLT1), peptide transporter 1 (PepT1), occludin, zonula occludens-1 (ZO-1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and interleukin-10 (IL-10), jejunal SGLT1, PepT1, occludin, tumor necrosis factor-α (TNF-α), and ileal SGLT1, PepT1, and fatty acid binding protein 1 (FABP1) was upregulated by COS. However, the expression level of duodenal FABP1 and TNF-α, jejunal GLUT1, ZO-1, TLR4, MyD88, nuclear factor kappa-B p65 (NF-κB p65), and IL-1ß, and ileal GLUT1, NF-κB p65, and IL-1ß was downregulated by COS. Furthermore, dietary COS supplementation increased duodenal catalase (CAT), glutathione peroxidase (GSH-Px), and total superoxide dismutase (T-SOD) activity, jejunal CAT and T-SOD activity, upregulated the expression level of duodenal nuclear factor-erythroid 2-related factor 2 (Nrf2), CAT, glutathione peroxidase 1 (GPX1), and copper and zinc superoxide dismutase (Cu/Zn SOD), jejunal CAT, and ileal Nrf2, CAT, and GPX1. These results suggested that COS could promote intestinal development and functions in broilers aged d 1 to 14, which might be mediated by alleviating intestinal inflammatory response and enhancing antioxidant capacity.

Anti-Colorectal Cancer Activity of Solasonin from Solanum nigrum L. via Histone Deacetylases-Mediated p53 Acetylation Pathway.

(1) Background: Solanum nigrum L. is a plant of the genus Solanum in the family Solanaceae and is commonly used to treat tumors. Solasonin (SS) is a steroidal alkaloid extracted from Solanum nigrum L. that has anti-colorectal cancer (CRC) activity. (2) Methods: Column chromatography, semi-preparative HPLC and cellular activity screening were used to isolate potential anti-CRC active compounds in Solanum nigrum L., and structure identification using 1H-NMR and 13C-NMR techniques. Expression levels of HDAC in CRC were mined in the UALCAN database. The in vitro effects of SS on SW620 cell line and its mechanism were examined via Western blot, EdU staining, flow cytometry and immunofluorescence. CRC xenograft model and IHC staining were mainly used to evaluate the role of SS in vivo. (3) Results: The results showed that SS was the most potent anti-CRC component in Solanum nigrum L., which induced apoptosis and cell cycle arrest in the SW620 cell line. HDAC was highly expressed in CRC. The treatment of SW620 cell line with SS resulted in a significant downregulation of HDAC, an increase in the level of P53 acetylation and a subsequent increase in the level of P21. The in vivo validation results showed that SS could effectively inhibit CRC growth, which was associated with the downregulation of HDAC. (4) Conclusions: SS treatment for CRC mainly works through the induction of apoptosis and cycle arrest, and its mechanism of action is mainly related to HDAC-induced P53 acetylation, and the HDAC/P53 signaling pathway may be a potential pathway for the treatment of CRC.

UPLC-MS/MS profiling, antioxidant and anti-inflammatory activities, and potential health benefits prediction of phenolic compounds in hazel leaf.

Hazel leaf, one of the by-products of hazelnut, which is widely used in traditional folk medicine around the world. In the present study, the profile of free, conjugated, and bound phenolic compounds from hazel leaf was detected and their antioxidant and anti-inflammatory activities were investigated. The potential health benefits of different phenolic compounds were also predicted. The results showed that the 35 phenolic substances of free, conjugated and bound forms were identified including phenolic acids, flavonoids and catechins. Most of the hazel leaf phenolics were presented in free form, followed by conjugated and bound form. All the fractions effectively inhibited the production of reactive oxygen species and malondialdehyde in TBHP-stimulated human umbilical vein endothelial cells by enhancing endogenous superoxide dismutase, and accordingly alleviated inflammatory cytokines (NO, IL-1ß, TNF-α, and IL-6) in LPS-stimulated RAW264.7 cells, showing obvious antioxidant and anti-inflammatory capacity. Moreover, combined with network pharmacology, the potential therapeutic effects and functional pathways of hazel leaf phenolics were predicted, which provided value basis for exploring their treatment on diseases and developing health products in the future.

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.

Functional Mechanism of Ginsenoside Compound K on Tumor Growth and Metastasis.

Ginsenosides, as the most important constituents of ginseng, have been extensively investigated in cancer chemoprevention and therapeutics. Among the ginsenosides, Compound K (CK), a rare protopanaxadiol type of ginsenoside, has been most broadly used for cancer treatment due to its high anticancer bioactivity. However, the functional mechanism of CK in cancer is not well known. This review describes the structure, transformation and pharmacological activity of CK and discusses the functional mechanisms of CK and its metabolites, which regulate signaling pathways related to tumor growth and metastasis. CK inhibits tumor growth by inducing tumor apoptosis and tumor cell differentiation, regulates the tumor microenvironment by suppressing tumor angiogenesis-related proteins, and downregulates the roles of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). There is currently much research on the potential development of CK as a new strategy when administered alone or in combination with other compounds.

[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.

Astragaloside IV Synergizing with Ferulic Acid Ameliorates Pulmonary Fibrosis by TGF-ß1/Smad3 Signaling.

OBJECTIVE: The study aims to research the interventional effect and mechanism of astragaloside IV (Ast) synergizing with ferulic acid (FA) on idiopathic pulmonary fibrosis (IPF) induced by bleomycin in mice. METHODS: The mice were randomly divided into seven groups with 10 mice in each group, namely, a sham operation group, a model group, a miRNA-29b (miR-29) group, a miR-29b negative control group (NC group), a FA group, an Ast group, and a combination group. A mouse model of pulmonary fibrosis was established by intratracheal instillation of bleomycin. Samples were collected after 28 days of continuous administration. Hematoxylin and eosin (HE) and Masson staining were used to observe pathological changes in the lung tissue, and the degree of fibrosis was evaluated using the hydroxyproline content. Changes in transforming growth factor-ß1 (TGF-ß1) and Smad3 in the lung were observed using immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) in the serum. PCR was used to detect the expression of the miR-29b, TGF-ß1, Smad3, and nuclear factor E2-related factor 2 (Nrf2) genes. Western blotting was used to detect the content of the TGF-ß/Smad3 protein. RESULTS: Ferulic acid combined with astragaloside IV reduced the degree of pulmonary fibrosis and the synthesis of hydroxyproline in lung tissue. The combination of the two also regulated the oxidative stress response ， TGF-ß1/Smad3 pathway and miR-29b in lung tissue. CONCLUSION: Astragaloside IV combined with ferulic acid regulated the oxidative stress of lung tissues and TGF-ß1/Smad3 signaling through miR-29b, thereby reducing the degree of pulmonary fibrosis. This provides a reference direction for the clinical treatment of IPF patients.

Impact of TCM on Tumor-Infiltrating Myeloid Precursors in the Tumor Microenvironment.

The tumor microenvironment (TME) is composed of tumor cells, blood/lymphatic vessels, the tumor stroma, and tumor-infiltrating myeloid precursors (TIMPs) as a sophisticated pathological system to provide the survival environment for tumor cells and facilitate tumor metastasis. In TME, TIMPs, mainly including tumor-associated macrophage (TAM), tumor-associated dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs), play important roles in repressing the antitumor activity of T cell or other immune cells. Therefore, targeting those cells would be one novel efficient method to retard cancer progression. Numerous studies have shown that traditional Chinese medicine (TCM) has made extensive research in tumor immunotherapy. In the review, we demonstrate that Chinese herbal medicine (CHM) and its components induce tumor cell apoptosis, directly inhibiting tumor growth and invasion. Further, we discuss that TCM regulates TME to promote effective antitumor immune response, downregulates the numbers and function of TAMs/MDSCs, and enhances the antigen presentation ability of mature DCs. We also review the therapeutic effects of TCM herbs and their ingredients on TIMPs in TME and systemically analyze the regulatory mechanisms of TCM on those cells to have a deeper understanding of TCM in tumor immunotherapy. Those investigations on TCM may provide novel ideas for cancer treatment.

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.

Pea-derived peptides, VLP, LLP, VA, and LL, improve insulin resistance in HepG2 cells via activating IRS-1/PI3K/AKT and blocking ROS-mediated p38MAPK signaling.

This study evaluated the effect of four peptides, VLP, LLP, LL, and LL from pea on regulating glucose metabolism and antioxidant through IRS-1/PI3K/AKT and p38MAPK signal pathway in IR-HepG2 cell induced by 10-6 M insulin. The genes expression of PEPCK, G6Pase, GLUT2, and IRS-1 and proteins of IRS-1, p(Ser307)-IRS-1, AKT, p(Ser473)-AKT, p38MAPK, and p-p38MAPK were determined by RT-PCR and western blotting, respectively. Results show that they displayed highly potent on stimulation glucose metabolism and relief oxidative stress in IR-HepG2 cells. VLP, LLP, VA, and LL reduced Ser307 phosphorylation of IRS-1 and promoted Ser473 phosphorylation of AKT. Among them, LLP, VA, and LL increased the expression both gene and protein of GLUT2, and VLP and LL reduced p38MAPK phosphorylation showing strong antioxidant capacity. Therefore, pea oligopeptides have considerable potential for reversing the metabolic abnormalities associated with type 2 diabetes. PRACTICAL APPLICATIONS: This paper examined the intervention effect of VLP, LLP, VA, and LL that from pea on insulin resistance, and the mechanisms were detected by western blotting. The results provide a theoretical knowledge for the prevention of insulin resistance in T2D of pea-derived peptides and lay the foundation for the development of functional products and drugs in the future.

Functional analysis of a novel C-glycosyltransferase in the orchid Dendrobium catenatum.

Flavonoids, which are a diverse class of phytonutrients, are used by organisms to respond to nearly all abiotic stresses and are beneficial for human health. Glycosyltransferase, used during the last step of flavonoid biosynthesis, is important in flavonoid enrichment. However, little is known about glycosyltransferase in the orchid Dendrobium catenatum (D. officinale). In this study, we isolated a novel C-glycosyltransferase (designated DcaCGT) from the orchid D. catenatum by identifying and analyzing 82 putative genes in the GT1 family. DcaCGT could specifically catalyze not only di-C-glycosylation but also O-glycosylation. Apart from the normal function of catalyzing 2-hydroxynaringenin and phloretin to the respective di-C-glycosides, DcaCGT also catalyzes apigenin to cosmosiin. Targeted metabolic profiling of the substrates (2-hydroxynaringenin, phloretin, and apigenin) and products (vitexin, isovitexin, vicenin-2, nothofagin, 3',5'-di-C-glucosylphloretin, and cosmosiin) in different tissues showed that vicenin-2 was the most abundant product of this novel enzyme. Cosmosiin was detected in flowers and flower buds. We also established that DcaCGT functions expanded throughout the evolution of D. catenatum. Residual OGT activity may help D. catenatum resist drought stress. Our study illustrates the function, origin, and differentiation of DcaCGT and provides insights into glycosylation and molecular propagation processes, which can be used to improve the production of flavonoids by the cultivated medicinal plant D. catenatum.

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.

Investigation of Crystal Structures in Structure-Based Virtual Screening for Protein Kinase Inhibitors.

Protein kinases are important drug targets in several therapeutic areas ,and structure-based virtual screening (SBVS) is an important strategy in discovering lead compounds for kinase targets. However, there are multiple crystal structures available for each target, and determining which one is the most favorable is a key step in molecular docking for SBVS due to the ligand induce-fit effect. This work aimed to find the most desirable crystal structures for molecular docking by a comprehensive analysis of the protein kinase database which covers 190 different kinases from all eight main kinase families. Through an integrated self-docking and cross-docking evaluation, 86 targets were eventually evaluated on a total of 2608 crystal structures. Results showed that molecular docking has great capability in reproducing conformation of crystallized ligands and for each target, the most favorable crystal structure was selected, and the AGC family outperformed the other family targets based on RMSD comparison. In addition, RMSD values, GlideScore, and corresponding bioactivity data were compared and demonstrated certain relationships. This work provides great convenience for researchers to directly select the optimal crystal structure in SBVS-based kinase drug design and further validates the effectiveness of molecular docking in drug discovery.

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.