Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.

Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca(2+) release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.

Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis.

Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e(-/-) mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.

Temporal variations of bacterial and eukaryotic community in coastal waters-implications for aquaculture.

Despite increased attention to the aquaculture environment, there is still a lack of understanding regarding the significance of water quality. To address this knowledge gap, this study utilized high-throughput sequencing of 16S rRNA and 18S rRNA to examine microbial communities (bacteria and eukaryotes) in coastal water over different months through long-term observations. The goal was to explore interaction patterns in the microbial community and identify potential pathogenic bacteria and red tide organisms. The results revealed significant differences in composition, diversity, and richness of bacterial and eukaryotic operational taxonomic units (OTUs) across various months. Principal coordinate analysis (PCoA) demonstrated distinct temporal variations in bacterial and eukaryotic communities, with significant differences (P = 0.001) among four groups: F (January-April), M (May), S (June-September), and T (October-December). Moreover, a strong association was observed between microbial communities and months, with most OTUs showing a distinct temporal preference. The Kruskal-Wallis test (P < 0.05) indicated significant differences in dominant bacterial and eukaryotic taxa among months, with each group exhibiting unique dominant taxa, including potential pathogenic bacteria and red tide organisms. These findings emphasize the importance of monitoring changes in potentially harmful microorganisms in aquaculture. Network analysis highlighted positive correlations between bacteria and eukaryotes, with bacteria playing a key role in network interactions. The key bacterial genera associated with other microorganisms varied significantly (P < 0.05) across different groups. In summary, this study deepens the understanding of aquaculture water quality and offers valuable insights for maintaining healthy aquaculture practices. KEY POINTS: • Bacterial and eukaryotic communities displayed distinct temporal variations. • Different months exhibited unique potential pathogenic bacteria and red tide organisms. • Bacteria are key taxonomic taxa involved in microbial network interactions.

The pattern of apolipoprotein A-I lysine carbamylation reflects its lipidation state and the chemical environment within human atherosclerotic aorta.

Protein lysine carbamylation is an irreversible post-translational modification resulting in generation of homocitrulline (N-ε-carbamyllysine), which no longer possesses a charged ε-amino moiety. Two distinct pathways can promote protein carbamylation. One results from urea decomposition, forming an equilibrium mixture of cyanate (CNO-) and the reactive electrophile isocyanate. The second pathway involves myeloperoxidase (MPO)-catalyzed oxidation of thiocyanate (SCN-), yielding CNO- and isocyanate. Apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoprotein (HDL), is a known target for MPO-catalyzed modification in vivo, converting the cardioprotective lipoprotein into a proatherogenic and proapoptotic one. We hypothesized that monitoring site-specific carbamylation patterns of apoA-I recovered from human atherosclerotic aorta could provide insights into the chemical environment within the artery wall. To test this, we first mapped carbamyllysine obtained from in vitro carbamylation of apoA-I by both the urea-driven (nonenzymatic) and inflammatory-driven (enzymatic) pathways in lipid-poor and lipidated apoA-I (reconstituted HDL). Our results suggest that lysine residues within proximity of the known MPO-binding sites on HDL are preferentially targeted by the enzymatic (MPO) carbamylation pathway, whereas the nonenzymatic pathway leads to nearly uniform distribution of carbamylated lysine residues along the apoA-I polypeptide chain. Quantitative proteomic analyses of apoA-I from human aortic atheroma identified 16 of the 21 lysine residues as carbamylated and suggested that the majority of apoA-I carbamylation in vivo occurs on "lipid-poor" apoA-I forms via the nonenzymatic CNO- pathway. Monitoring patterns of apoA-I carbamylation recovered from arterial tissues can provide insights into both apoA-I structure and the chemical environment within human atheroma.

DelaySSAToolkit.jl: stochastic simulation of reaction systems with time delays in Julia.

SUMMARY: DelaySSAToolkit.jl is a Julia package for modelling reaction systems with non-Markovian dynamics, specifically those with time delays. These delays implicitly capture multiple intermediate reaction steps and hence serve as an effective model reduction technique for complex systems in biology, chemistry, ecology and genetics. The package implements a variety of exact formulations of the delay stochastic simulation algorithm. AVAILABILITY AND IMPLEMENTATION: The source code and documentation of DelaySSAToolkit.jl are available at https://github.com/palmtree2013/DelaySSAToolkit.jl.

Rational Design, Synthesis, and Anti-Proliferative Evaluation of Novel 4-Aryl-3,4-Dihydro-2H-1,4-Benzoxazines.

A synthetic pathway to a novel 4-aryl-3,4-dihydro-2H-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a para-amino group on ring C significantly enhanced potency. Molecule 14f displayed the most potent anticancer activity (IC50 = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.

Dynamic Growth of Macroscopically Structured Supramolecular Hydrogels through Orchestrated Reaction-Diffusion.

Living organisms are capable of dynamically changing their structures for adaptive functions through sophisticated reaction-diffusion processes. Here we show how active supramolecular hydrogels with programmable lifetimes and macroscopic structures can be created by relying on a simple reaction-diffusion strategy. Two hydrogel precursors (poly(acrylic acid) PAA/CaCl2 and Na2 CO3 ) diffuse from different locations and generate amorphous calcium carbonate (ACC) nanoparticles at the diffusional fronts, leading to the formation of hydrogel structures driven by electrostatic interactions between PAA and ACC nanoparticles. Interestingly, the formed hydrogels are capable of autonomously disintegrating over time because of a delayed influx of electrostatic-interaction inhibitors (NaCl). The hydrogel growth process is well explained by a reaction-diffusion model which offers a theoretical means to program the dynamic growth of structured hydrogels. Furthermore, we demonstrate a conceptual access to dynamic information storage in soft materials using the developed reaction-diffusion strategy. This work may serve as a starting point for the development of life-like materials with adaptive structures and functionalities.

Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk.

Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.

A cell-cell repulsion model on a hyperbolic Keller-Segel equation.

In this work, we discuss a cell-cell repulsion model based on a hyperbolic Keller-Segel equation with two populations, which aims at describing the cell growth and dispersion in the co-culture experiment from the work of Pasquier et al. (Biol Direct 6(1):5, 2011). We introduce the notion of solution integrated along the characteristics, which allows us to prove the existence and uniqueness of solutions and the segregation property for the two species. From a numerical perspective, we also observe that our model admits a competitive exclusion principle which is different from the classical competitive exclusion principle for the corresponding ODE model. More importantly, our model shows the complexity of the short term (6 days) co-cultured cell distribution depending on the initial distribution of each species. Through numerical simulations, we show that the impact of the initial distribution on the proportion of each species in the final population lies in the initial number of cell clusters and that the final proportion of each species is not influenced by the precise distribution of the initial distribution. We also find that a fast dispersion rate gives a short-term advantage while the vital dynamics contributes to a long-term population advantage. When the initial condition for the two species is not segregated, the numerical simulations suggest that asymptotic segregation occurs when the dispersion coefficients are not equal for two populations.

The prevalence of dental anxiety and its association with pain and other variables among adult patients with irreversible pulpitis.

BACKGROUND: The aim is to investigate the prevalence of dental anxiety and its association with pain and other related factors in adult patients with irreversible pulpitis. METHODS: One hundred and thirty patients with irreversible pulpitis were included in this cross-sectional study. Participants were asked to fill out an information table and a battery of questionnaires to assess their level of dental anxiety, pain at their first and most recent dental experience, and pain intensity before/during the present endodontic treatment. The level of anxiety that participants displayed during the present treatment was also evaluated by the dentists using an anxiety rating scale. Data were analyzed by t-test, ANOVA, and Spearman correlation tests. RESULTS: 83.1% of participants suffered from moderate or high dental anxiety, and 16.2% met criteria for specific phobia. Subjects who had higher MDAS scores were more likely to postpone their dental visits (P < 0.05). Subjects who had bad experiences at their most recent dental visit were more anxious (P < 0.05). Pain at the most recent dental visit (P < 0.01) or before the present dental visit (P < 0.05) was important factor correlating with dental anxiety among participants. Notably, 36.2% of participants displayed moderate or severe anxiety during this present visit for endodontic treatment based on dentist's judgement. CONCLUSIONS: A high percentage of people with irreversible pulpitis suffer from dental anxiety. Pain at the most recent dental visit and during endodontic treatment have strongly positive association with dental anxiety. Effective pain control in endodontics is beneficial to manage the anxiety.

Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine.

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl2 application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration.NEW & NOTEWORTHY Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.

BACKGROUND: Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans. METHODS: We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. RESULTS: Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups. CONCLUSIONS: The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).

Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide.

AIMS: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. METHODS AND RESULTS: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)µM, 9.8 (7.9-12.2)µM, and 41.1 (32.5-52.1)µM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. CONCLUSION: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a Toll-like receptor 2-mediated cell-penetrating peptide.

Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In our study, enhanced expression of toll-like receptor 2 (TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding peptide motif, Pep2. We show that the TLR2-binding peptide motif targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2 expression (TLR2(high)) but not in chronic myeloid leukemia (CML) cells with low TLR2 expression (TLR2(low)). The antileukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2(high) AML compared to TLR2(low) CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2 is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.

Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.

Protein carbamylation predicts mortality in ESRD.

Traditional risk factors fail to explain the increased risk for cardiovascular morbidity and mortality in ESRD. Cyanate, a reactive electrophilic species in equilibrium with urea, posttranslationally modifies proteins through a process called carbamylation, which promotes atherosclerosis. The plasma level of protein-bound homocitrulline (PBHCit), which results from carbamylation, predicts major adverse cardiac events in patients with normal renal function, but whether this relationship is similar in ESRD is unknown. We quantified serum PBHCit in a cohort of 347 patients undergoing maintenance hemodialysis with 5 years of follow-up. Kaplan-Meier analyses revealed a significant association between elevated PBHCit and death (log-rank P<0.01). After adjustment for patient characteristics, laboratory values, and comorbid conditions, the risk for death among patients with PBHCit values in the highest tertile was more than double the risk among patients with values in the middle tertile (adjusted hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5-3.9) or the lowest tertile (adjusted HR, 2.3; 95% CI, 1.5-3.7). Including PBHCit significantly improved the multivariable model, with a net reclassification index of 14% (P<0.01). In summary, serum PBHCit, a footprint of protein carbamylation, predicts increased cardiovascular risk in patients with ESRD, supporting a mechanistic link among uremia, inflammation, and atherosclerosis.

[Mycelium of Hirsutella hepiali Chen et Shen activates autophagy and protects against metabolic syndrome in mice fed with high fat diet].

To investigate the protective effects and possible mechanism of Mycelium of Hirsutella hepiali Chen et Shen (MHCS) on metabolic syndromes, free fatty acid and MHCS-treated hepatocytes were used for detecting autophagy-related LC3, p62 and lipid accumulation. Moreover, high fat diet fed mice were used to establish metabolic syndromes model. 50-weeks age mice were randomly divided into: control group, model group and MHCS group. At 80-weeks age, 15 mice were randomly chosen from each group separately for examining oral glucose tolerance, serum insulin, insulin-like growth factor 1 (IGF-1), hepatic LC3, p62, p-NF-kappaB p65, NF-kappaB p65, IL-6 and CXCL-8. Moreover, insulin resistance index (IRI) was calculated. Hepatic pathological changes, including vacuoles, lipids accumulation and fibrosis were observed. Remaining mice were fed with diet separately to 110 weeks-age for statistics of mortality. MHCS promoted autophagy of free fatty acid treated hepatocytes. Mice fed with high fat plus MHCS diet exhibited improved oral glucose tolerance, insulin resistance, hepatic pathology, inflammation, mortality and activated autophagy. The protective effects of MHCS against metabolic syndroms might be through the activation of hepatic autophagy.

Autonomous and policy-induced behavior change during the COVID-19 pandemic: Towards understanding and modeling the interplay of behavioral adaptation.

Changes in human behaviors, such as reductions of physical contacts and the adoption of preventive measures, impact the transmission of infectious diseases considerably. Behavioral adaptations may be the result of individuals aiming to protect themselves or mere responses to public containment measures, or a combination of both. What drives autonomous and policy-induced adaptation, how they are related and change over time is insufficiently understood. Here, we develop a framework for more precise analysis of behavioral adaptation, focusing on confluence, interactions and time variance of autonomous and policy-induced adaptation. We carry out an empirical analysis of Germany during the fall of 2020 and beyond. Subsequently, we discuss how behavioral adaptation processes can be better represented in behavioral-epidemiological models. We find that our framework is useful to understand the interplay of autonomous and policy-induced adaptation as a "moving target". Our empirical analysis suggests that mobility patterns in Germany changed significantly due to both autonomous and policy-induced adaption, with potentially weaker effects over time due to decreasing risk signals, diminishing risk perceptions and an erosion of trust in the government. We find that while a number of simulation and prediction models have made great efforts to represent behavioral adaptation, the interplay of autonomous and policy-induced adaption needs to be better understood to construct convincing counterfactual scenarios for policy analysis. The insights presented here are of interest to modelers and policy makers aiming to understand and account for behaviors during a pandemic response more accurately.

A sono-responsive antibacterial nanosystem co-loaded with metformin and bone morphogenetic protein-2 for mitigation of inflammation and bone loss in experimental peri-implantitis.

Background: Dental implants have become an increasingly popular option for replacing missing teeth, and the prevalence of peri-implantitis has also increased, which is expected to become a public health problem worldwide and cause high economic and health burdens. This scenario highlights the need for new therapeutic options to treat peri-implantitis. Methods: In this study, we proposed a novel sono-responsive antibacterial nanosystem co-loaded with metformin (Met) and bone morphogenetic protein-2 (BMP-2) to promote efficacy in treating peri-implantitis. We introduced the zeolitic imidazolate framework-8 (ZIF-8) as a carrier for hematoporphyrin monomethyl ether (HMME) to enhance the antibacterial effect of sonodynamic antibacterial therapy and tested its reactive oxygen species (ROS) production efficiency and bactericidal effect in vitro. Afterward, HMME-loaded ZIF-8, BMP-2-loaded polylactic acid-glycolic acid (PLGA), and Met were incorporated into gelatin methacryloyl (GelMA) hydrogels to form HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels, and the biocompatibility of which was determined in vitro and in vivo. A bacterial-induced peri-implantitis model in the maxilla of rats was established to detect the effects of the composite hydrogels with adjunctive use of ultrasound on regulating inflammation and promoting bone tissue repair in vivo. Results: The results indicated that HMME@ZIF-8 with ultrasound stimulation demonstrated more better ROS production efficiency and antimicrobial efficacy. The composite hydrogels had good biocompatibility. Ultrasound-assisted application of the composite hydrogels reduced the release of the inflammatory factors IL-6 and TNF-α and reduced bone loss around the implant in rats with bacterial-induced peri-implantitis. Conclusion: Our observations suggest that HMME@ZIF-8 may be a new good sonosensitizer material for sonodynamic antibacterial therapy. The use of HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels in combination with ultrasound can provide a novel option for treating peri-implantitis in the future.