Tunable Stochastic State Switching in 2D MoS2 Nanomechanical Resonators with Nonlinear Mode Coupling and Internal Resonance.

Coupled nanomechanical resonators have unveiled fascinating physical phenomena, including phonon-cavity coupling, coupled energy decay pathway, avoided crossing, and internal resonance. Despite these discoveries, the mechanisms and control techniques of nonlinear mode coupling phenomena with internal resonances require further exploration. Here, we report on the observation of stochastic switching between the two resonance states with coupled 1:1 internal resonance, for resonant two-dimensional (2D) molybdenum disulfide (MoS2) nanoelectromechanical systems (NEMS), which is directly driven to the critical coupling regime without parametric pumping. We further demonstrate that the probability of state switching is linearly tunable from ∼0% to ∼100% by varying the driving voltage. Furthermore, we gradually increase the white noise amplitude and show that the probability of obtaining the higher-energy state decreases, and the stochastic switching phenomenon eventually disappears. The results provide insights into the dynamics of coupled NEMS resonators and open up new possibilities for sensing and stochastic computing.

Probing Linear to Nonlinear Damping in 2D Semiconductor Nanoelectromechanical Resonators toward a Unified Quality Factor Model.

In resonant nanoelectromechanical systems (NEMS), the quality (Q) factor is essential for sensing, communication, and computing applications. While a large vibrational amplitude is useful for increasing the signal-to-noise ratio, the damping in this regime is more complex because both linear and nonlinear damping are important, and an accurate model for Q has not been fully explored. Here, we demonstrate that by combining the time-domain ringdown and frequency-domain resonance measurements, we extract the accurate Q for two-dimensional (2D) MoS2 and MoTe2 NEMS resonators at different vibration amplitudes. In particular, in the transition region between linear and nonlinear damping, Q can be precisely extracted by fitting to the ringdown characteristics. By varying AC driving, we tune the Q by ΔQ/Q = 269% and extract the nonlinear damping coefficient. We develop the dissipation model that well captures the linear to nonlinear damping, providing important insights for accurately modeling and optimizing Q in 2D NEMS resonators.

Raman Spectroscopic Probe for Nonlinear MoS2 Nanoelectromechanical Resonators.

Resonant nanoelectromechanical systems (NEMS) enabled by two-dimensional (2D) semiconductors have been actively explored and engineered for making ultrascaled transducers toward applications in ultralow-power signal processing, communication, and sensing. Although the transduction of miniscule resonant motions has been achieved by low-noise optical or electronic techniques, direct probing of strain in vibrating 2D semiconductor membranes and the interplay between the spectroscopic and mechanical properties are still largely unexplored. Here, we experimentally demonstrate dynamical phonon softening in atomically thin molybdenum disulfide (MoS2) NEMS resonators by directly coupling Raman spectroscopy with optical interferometry resonance motion detection. In single-layer, bilayer, and trilayer (1L to 3L) MoS2 circular membrane NEMS resonators, we show that high-amplitude nonlinear resonances can enhance the Raman signal amplitude, as well as introduce Raman modes softening up to 0.8 cm-1. These results shall pave the way for engineering the coupling and control between collective mechanical vibrations and Raman modes of the constituent crystals in 2D transducers.

Acute Coronary Syndrome May be Associated with Decreased Resolvin D1-to-Leukotriene B4 Ratio.

An imbalance between inflammation-resolving lipid mediators and proinflammatory leukotrienes with the instability of atherosclerotic plaques in experimental models has been reported. However, the contribution of the balance of Resolvin D1 (RvD1) to Leukotriene B4 (LTB4) in predicting acute coronary syndrome (ACS) remains unknown. This study investigated the association of RvD1-to-LTB4 ratio with ACS.Eighty-one patients with ACS and 90 stable coronary artery disease (SCAD) patients were included in this study. Plasma RvD1 and LTB4 levels were measured with commercial kits.Patients with ACS had higher LTB4 levels, lower RvD1 levels, and a lower RvD1-to-LTB4 ratio than patients with SCAD. History of diabetes mellitus, elevated Troponin I, LTB4, and decreased RvD1-to-LTB4 ratio (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.014-1.040; P < 0.001) were independently correlated with ACS. Receiver operating characteristic curve analysis demonstrated that RvD1-to-LTB4 ratio was a potential biomarker for the risk of ACS.A circulating proinflammatory lipid profile, characterized by a low RvD1-to-LTB4 ratio may be associated with ACS in patients with ischemic heart disease.

Ezetimibe Improves Rosuvastatin Effects on Inflammation and Vascular Endothelial Function in Acute Coronary Syndrome Patients Undergoing PCI.

BACKGROUND: Little is known of the acute effects of ezetimibe in patients with acute coronary syndrome (ACS) undergoing PCI. We investigated whether ezetimibe improves inflammation and vascular endothelial function in patients with ACS undergoing PCI. METHODS: We randomized 171 patients with ACS undergoing PCI to receive ezetimibe 10 mg/day plus rosuvastatin 20 mg/day (combination group, n = 81) versus rosuvastatin 20 mg/day (rosuvastatin group, n = 90). Lipid profile, type II secretory phospholipase A2 (sPLA2-IIa), interleukin-1ß (IL-1ß), vascular cell adhesion molecule-1 (VCAM-1), and intercellular cell adhesion molecule-1 (ICAM-1) were measured at baseline and after 7 days. Three months after PCI, clinical outcomes were examined. RESULT: The levels of sPLA2-IIa and IL-1ß reduced significantly in both groups, but more when ezetimibe and rosuvastatin were coadministered (sPLA2-IIa: 6.16 ± 2.67 vs. 7.42 ± 3.53 ng/ml, p=0.01; IL-1ß: 37.39 ± 26.25 vs. 48.98 ± 32.26 pg/ml, p=0.01). A significant rise of VCAM-1 and ICAM-1 was observed on day 7 after PCI in the both groups, but was less in the combination group (VCAM-1: 918.28 ± 235.31 vs. 988.54 ± 194.41 ng/ml, p=0.03; ICAM-1: 213.01 ± 100.15 vs. 246.88 ± 105.71 ng/ml, p=0.03). Patients in the combination versus rosuvastatin group appeared to suffer from less major adverse events. Periprocedural therapy of ezetimibe improves rosuvastatin effects on proinflammatory responses and endothelial function associated with ACS patients undergoing PCI. This trial is registered with https://clinicaltrials.gov/ct2/show/ChiCTR-IPR-17012219 (Chinese Clinical Trial Registry, http://www.chictr.org.cn on 02/08/2017).

Association of sputum microbiome with clinical outcome of initial antibiotic treatment in hospitalized patients with acute exacerbations of COPD.

Identification of risk factors for antibiotic treatment failure is urgently needed in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Here we investigated the relationship between sputum microbiome and clinical outcome of choice of initial antibiotics during hospitalization of AECOPD patients. Sputum samples of 41 AECOPD patients and 26 healthy controls were collected from Guangzhou Medical University, China. Samples were processed for 16S rRNA gene-based microbiome profiling. Thirty patients recovered with initial antibiotic treatment (antibiotic success or AS), while 11 patients showed poor outcome (antibiotic failure or AF). Substantial differences in microbiome were observed in AF versus AS patients and healthy controls. There was significantly decreased alpha diversity and increased relative abundances of Pseudomonas, Achromobacter, Stenotrophomonas and Ralstonia in AF patients. Conversely, Prevotella, Peptostreptococcus, Leptotrichia and Selenomonas were depleted. The prevalence of Selenomonas was markedly reduced in AF versus AS patients (9.1 % versus 60.0 %, P = 0.004). The AF patients with similar microbiome profiles in general responded well to the same new antibiotics in the adjusted therapy, indicating sputum microbiome may help guide the adjustment of antibiotics. Random forest analysis identified five microbiome operational taxonomic units together with C-reactive protein, procalcitonin and blood neutrophil count showing best predictability for antibiotic treatment outcome (area under curve 0.885). Functional inference revealed an enrichment of microbial genes in xenobiotic metabolism and antimicrobial resistance in AF patients, whereas genes in DNA repair and amino acid metabolism were depleted. Sputum microbiome may determine the clinical outcome of initial antibiotic treatment and be considered in the risk management of antibiotics in AECOPD.

Alterations in gut microbiota of abdominal aortic aneurysm mice.

BACKGROUND: The gut microbiome plays an important role in various cardiovascular diseases, such as atherosclerosis and hypertension, which are associated with abdominal aortic aneurysms (AAAs). METHODS: Here, we used 16S rRNA sequencing to explore gut microbiota in C57BL ApoE-/- mice with AAAs. A mouse model of abdominal aortic aneurysms was induced with angiotensin II (Ang II) (1000 ng/min per kg). On day 28 after the operation, fecal samples were collected and stored at - 80 °C until DNA extraction. We determined the relative abundances of bacterial taxonomic groups using 16S rRNA amplicon metabarcoding, and sequences were analyzed using a combination of mother software and UPARSE. RESULTS: We found that the gut microbiome was different between control and AAA mice. The results of correlation analysis between AAA diameter and the gut microbiome as well as LEfSe of the genera Akkermansia, Odoribacter, Helicobacter and Ruminococcus might be important in the progression of AAAs. CONCLUSIONS: AAA mice is subjected to gut microbial dysbiosis, and gut microbiota might be a potential target for further investigation.

Metformin Increases Cardiac Rupture After Myocardial Infarction via the AMPK-MTOR/PGC-1α Signaling Pathway in Rats with Acute Myocardial Infarction.

BACKGROUND Cardiac rupture often occurs after acute myocardial infarction due to complex and unclear pathogenesis. This study investigated whether metformin increases the incidence of cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway. MATERIAL AND METHODS An acute myocardial infarction (MI) mouse model was established. A series of experiments involving RT-qPCR, Western blot, TUNEL staining, and Masson staining were performed in this study. RESULTS Myocardial infarction occurred, resulting in the cardiac rupture, and the expression level of PGC-1α increased in the cardiac myocardium. Meanwhile, the proportion of myocardial NT-PGC-1α/PGC-1α decreased. The expression level of myocardial PGC-1α in MI mice with cardiac rupture after MI was significantly higher than that in the mice without cardiac rupture, and the ratio of myocardial NT-PGC-1α/PGC-1α was low. In addition, increasing the dose of metformin significantly increased the incidence of cardiac rupture after myocardial infarction in MI mice. High-dose metformin caused cardiac rupture in MI mice. Moreover, high-dose metformin (Met 2.0 nM) reduces the proportion of NT-PGC-1α/PGC-1α in primary cardiomyocytes of SD mice (SD-NRVCs [Neonatal rat ventricular cardiomyocytes]), and its effect was inhibited by Compound C (AMPK inhibitor). Further, after 3 days of treatment with high-dose metformin in MI mice, myocardial fibrin synthesis decreased and fibrosis was significantly inhibited. Meanwhile, cardiomyocyte apoptosis increased significantly. With the increase in metformin concentration, the expression level of myocardial LC3b gradually increased in MI mice, suggesting that metformin enhances the autophagy of cardiomyocytes. CONCLUSIONS These results suggest that metformin increases cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.

Unveiling the tradeoff between device scale and surface nonidealities for an optimized quality factor at room temperature in 2D MoS2 nanomechanical resonators.

A high quality (Q) factor is essential for enhancing the performance of resonant nanoelectromechanical systems (NEMS). NEMS resonators based on two-dimensional (2D) materials such as molybdenum disulfide (MoS2) have high frequency tunability, large dynamic range, and high sensitivity, yet room-temperature Q factors are typically less than 1000. Here, we systematically investigate the effects of device size and surface nonidealities on Q factor by measuring 52 dry-transferred fully clamped circular MoS2 NEMS resonators with diameters ranging from 1 µm to 8 µm, and optimize the Q factor by combining these effects with the strain-modulated dissipation model. We find that Q factor first increases and then decreases with diameter, with an optimized room-temperature Q factor up to 3315 ± 115 for a 2-µm-diameter device. Through extensive characterization and analysis using Raman spectroscopy, atomic force microscopy, and scanning electron microscopy, we demonstrate that surface nonidealities such as wrinkles, residues, and bubbles are especially significant for decreasing Q factor, especially for larger suspended membranes, while resonators with flat and smooth surfaces typically have larger Q factors. To further optimize Q factors, we measure and model Q factor dependence on the gate voltage, showing that smaller DC and radio-frequency (RF) driving voltages always lead to a higher Q factor, consistent with the strain-modulated dissipation model. This optimization of the Q factor delineates a straightforward and promising pathway for designing high-Q 2D NEMS resonators for ultrasensitive transducers, efficient RF communications, and low-power memory and computing.

Dietary inflammation influences the prevalence of cardiovascular diseases in prediabetes and diabetes patients: findings from the National Health and Nutrition Examination Survey (NHANES 2001-2018).

Prediabetes is an early phase before diabetes. Diabetes and dietary inflammation are two crucial factors that are strongly associated with cardiovascular diseases (CVDs). Dietary interventions slowed the progression of diabetes and CVD. However, the associations between CVDs and dietary inflammation in different stages of pathoglycaemia have not been investigated. To explore the effect of a proinflammatory diet on CVD incidence at different stages of diabetes, NHANES (2001-2018) data were collected and analysed. A total of 3137 CVD patients with a comparable non-CVD group (n = 3137) were enrolled after propensity score matching (PSM) analysis. These patients were subsequently categorized into three subgroups: those with diabetes (n = 3043), those with prediabetes (n = 1099) and those with normoglycemia (n = 2132). The DII (Dietary inflammatory index) is a risk factor for CVD, both in overall individuals and in each subgroup of population-based information. In diabetic individuals, the odds ratios (ORs) (95% CIs) of CVD incidence for the DII were 1.10 (1.05, 1.15) and 1.08 (1.03, 1.13) according to the crude and adjusted models, respectively. For individuals with prediabetes, the ORs (95% CIs) of CVD risk for DII were 1.05 (0.97, 1.14) and 1.11 (1.01, 1.22) according to the crude and adjusted models, respectively. After adjusting for population-based information and hypertension status, the DII appeared to have the highest OR for individuals with prediabetes, and no significant association was found between the DII score and CVD risk in the normoglycemia group. Moreover, the OR of CVD for DII in the uncontrolled diabetes group was 1.06 (0.98, 1.16)*. These results suggest that the DII is more closely associated with the risk of CVDs in prediabetic and diabetic populations, and we should pay more attention to diet control before a person develops diabetes to prevent CVD progression.

Research development on gut microbiota and vulnerable atherosclerotic plaque.

The relationship between gut microbiota and its metabolites with cardiovascular disease (CVD) has been proven. In this review, we aim to conclude the potential mechanism of gut microbiota and its metabolites on inducing the formation of vulnerable atherosclerotic plaque, and to discuss the effect of intestinal metabolites, including trimethylamine-N-oxide (TMAO), lipopolysaccharide (LPS), phenylacetylglutamine (PAG), short-chain fatty acids (SCFAs) on plaque stability. Finally, we include the impact of gut microbiota and its metabolites on plaque stability, to propose a new therapeutic direction for coronary heart disease. Gut microbiota regulation intervenes the progress of arteriosclerosis, especially on coronary atherosclerosis, by avoiding or reducing the formation of vulnerable plaque, to lower the morbidity rate of myocardial infarction.

Episode of ventricular fibrillation in patient with coronary artery ectasia during coronary angiography.

There was an 83-year-old man having coronary artery disease associated with coronary artery ectasia who occurred ventricular fibrillation suddenly during coronary artery angiography. As Kawasaki disease was suspected to the most likely reason which led to coronary artery lesion.

Monolithic 3D integration of 2D transistors and vertical RRAMs in 1T-4R structure for high-density memory.

Emerging data-intensive computation has driven the advanced packaging and vertical stacking of integrated circuits, for minimized latency and energy consumption. Yet a monolithic three-dimensional (3D) integrated structure with interleaved logic and high-density memory layers has been difficult to achieve due to challenges in managing the thermal budget. Here we experimentally demonstrate a monolithic 3D integration of atomically-thin molybdenum disulfide (MoS2) transistors and 3D vertical resistive random-access memories (VRRAMs), with the MoS2 transistors stacked between the bottom-plane and top-plane VRRAMs. The whole fabrication process is integration-friendly (below 300 °C), and the measurement results confirm that the top-plane fabrication does not affect the bottom-plane devices. The MoS2 transistor can drive each layer of VRRAM into four resistance states. Circuit-level modeling of the monolithic 3D structure demonstrates smaller area, faster data transfer, and lower energy consumption than a planar memory. Such platform holds a high potential for energy-efficient 3D on-chip memory systems.

Metformin Collaborates with PINK1/Mfn2 Overexpression to Prevent Cardiac Injury by Improving Mitochondrial Function.

Both mitochondrial quality control and energy metabolism are critical in maintaining the physiological function of cardiomyocytes. When damaged mitochondria fail to be repaired, cardiomyocytes initiate a process referred to as mitophagy to clear defective mitochondria, and studies have shown that PTEN-induced putative kinase 1 (PINK1) plays an important role in this process. In addition, previous studies indicated that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that promotes mitochondrial energy metabolism, and mitofusin 2 (Mfn2) promotes mitochondrial fusion, which is beneficial for cardiomyocytes. Thus, an integration strategy involving mitochondrial biogenesis and mitophagy might contribute to improved cardiomyocyte function. We studied the function of PINK1 in mitophagy in isoproterenol (Iso)-induced cardiomyocyte injury and transverse aortic constriction (TAC)-induced myocardial hypertrophy. Adenovirus vectors were used to induce PINK1/Mfn2 protein overexpression. Cardiomyocytes treated with isoproterenol (Iso) expressed high levels of PINK1 and low levels of Mfn2, and the changes were time dependent. PINK1 overexpression promoted mitophagy, attenuated the Iso-induced reduction in MMP, and reduced ROS production and the apoptotic rate. Cardiac-specific overexpression of PINK1 improved cardiac function, attenuated pressure overload-induced cardiac hypertrophy and fibrosis, and facilitated myocardial mitophagy in TAC mice. Moreover, metformin treatment and PINK1/Mfn2 overexpression reduced mitochondrial dysfunction by inhibiting ROS generation leading to an increase in both ATP production and mitochondrial membrane potential in Iso-induced cardiomyocyte injury. Our findings indicate that a combination strategy may help ameliorate myocardial injury by improving mitochondrial quality.

Implantable QR code subcutaneous microchip using photoacoustic and ultrasound microscopy for secure and convenient individual identification and authentication.

Individual identification and authentication techniques are merged into many aspects of human life with various applications, including access control, payment or banking transfer, and healthcare. Yet conventional identification and authentication methods such as passwords, biometrics, tokens, and smart cards suffer from inconvenience and/or insecurity. Here, inspired by quick response (QR) code and implantable microdevices, implantable and minimally-invasive QR code subcutaneous microchips (QRC-SMs) are proposed to be an effective approach to carry useful and private information, thus enabling individual identification and authentication. Two types of QRC-SMs, QRC-SMs with "hole" and "flat" elements and QRC-SMs with "titanium-coated" and "non-coated" elements, are designed and fabricated to store personal information. Corresponding ultrasound microscopy and photoacoustic microscopy are used for imaging the QR code pattern underneath skin, and open-source artificial intelligence algorithm is applied for QR code detection and recognition. Ex vivo experiments under tissue and in vivo experiments with QRC-SMs implanted in live mice have been performed, demonstrating successful information retrieval from implanted QRC-SMs. QRC-SMs are hidden subcutaneously and invisible to the eyes. They cannot be forgotten, misplaced or lost, and can always be ready for timely medical identification, access control, and payment or banking transfer. Hence, QRC-SMs provide promising routes towards private, secure, and convenient individual identification and authentication.

The airway microbiome mediates the interaction between environmental exposure and respiratory health in humans.

Exposure to environmental pollution influences respiratory health. The role of the airway microbial ecosystem underlying the interaction of exposure and respiratory health remains unclear. Here, through a province-wide chronic obstructive pulmonary disease surveillance program, we conducted a population-based survey of bacterial (n = 1,651) and fungal (n = 719) taxa and metagenomes (n = 1,128) from induced sputum of 1,651 household members in Guangdong, China. We found that cigarette smoking and higher PM2.5 concentration were associated with lung function impairment through the mediation of bacterial and fungal communities, respectively, and that exposure was associated with an enhanced inter-kingdom microbial interaction resembling the pattern seen in chronic obstructive pulmonary disease. Enrichment of Neisseria was associated with a 2.25-fold increased risk of high respiratory symptom burden, coupled with an elevation in Aspergillus, in association with occupational pollution. We developed an individualized microbiome-based health index, which covaried with exposure, respiratory symptoms and diseases, with potential generalizability to global datasets. Our results may inform environmental risk prevention and guide interventions that harness airway microbiome.

Strain-Modulated Dissipation in Two-Dimensional Molybdenum Disulfide Nanoelectromechanical Resonators.

Resonant nanoelectromechanical systems (NEMS) based on two-dimensional (2D) materials such as molybdenum disulfide (MoS2) are interesting for highly sensitive mass, force, photon, or inertial transducers, as well as for fundamental research approaching the quantum limit, by leveraging the mechanical degree of freedom in these atomically thin materials. For these mechanical resonators, the quality factor (Q) is essential, yet the mechanism and tuning methods for energy dissipation in 2D NEMS resonators have not been fully explored. Here, we demonstrate that by tuning static strain and vibration-induced strain in suspended MoS2 using gate voltages, we can effectively tune the Q in 2D MoS2 NEMS resonators. We further show that for doubly clamped resonators, the Q increases with larger DC gate voltage, while fully clamped drumhead resonators show the opposite trend. Using DC gate voltages, we can tune the Q by ΔQ/Q = 448% for fully clamped resonators, and by ΔQ/Q = 369% for doubly clamped resonators. We develop the strain-modulated dissipation model for these 2D NEMS resonators, which is verified against our measurement data for 8 fully clamped resonators and 7 doubly clamped resonators. We find that static tensile strain decreases dissipation while vibration-induced strain increases dissipation, and the actual dependence of Q on DC gate voltage depends on the competition between these two effects, which is related to the device boundary condition. Such strain dependence of Q is useful for optimizing the resonance linewidth in 2D NEMS resonators toward low-power, ultrasensitive, and frequency-selective devices for sensing and signal processing.

Exploring the role of uterine fibroids in promotion of cardiovascular diseases by diabetes exposure: Findings from national health and nutrition examination survey 1999-2006.

Objective: The relationship between uterine fibroids (UF) and cardiovascular diseases (CVDs) in the diabetes population seemed to remain undetermined in previous studies. This study aims to explore the association between UF and CVDs by using the database from the National Health and Nutrition Examination Survey (NHANES). To further evaluate the connection between UF and CVDs we also tested the potential differences due to diabetes exposure. Materials and methods: National Health and Nutrition Examination Survey data (1999-2006) were collected and used in this study. A total of 5,509 individuals were included and analyzed. The student's t-test and the chi-squared test were used to explore the demographic characteristic between UF and non-UF groups. Logistic regression analysis was performed to determine the odds ratios of UF and covariates. Results: Female participants were divided into UF (n = 694, 12.60%) and non-UF (n = 4,815, 87.40%) groups. The incidence of CVDs in UF patients (n = 245, 35.30%) were higher than non-UF individuals (n = 776, 16.12%) (p < 0.001). In addition, each subtype of CVDs were also different, which contains hypertension (33.29 vs. 15.31%, p < 0.001), heart failure (1.59 vs. 0.52%, p < 0.01), angina (2.59 vs. 0.62%, p < 0.001), heart attack (1.73 vs. 0.58%, p < 0.01) and coronary heart disease (1.44 vs. 0.54%, p < 0.01). The odds ratios of CVDs according to logistic regression were 2.840 (95% CI: 2.387-3.379) for UF patients (p < 0.001), while the odds ratios (ORs) were 1.438 (95% CI: 1.175-1.760) after taking account for the age, body mass index (BMI), diabetes, race, education, and annual family income (p < 0.001). In addition, secondary analysis indicated more adverse effects in by UF exposure on CVDs risk among non-diabetes individuals (OR = 1.389, 95% CI = 1.124-1.718, p < 0.01) than diabetes patients (p = 0.063). Conclusion: Overall, UFs were positively associated with CVDs, and this effect seems blunted by diabetes exposure.

Trimethylamine N-oxide induces osteogenic responses in human aortic valve interstitial cells in vitro and aggravates aortic valve lesions in mice.

AIMS: Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. METHODS AND RESULTS: Plasma TMAO levels were higher in patients with CAVD (n = 69) than in humans without CAVD (n = 263), as examined by liquid chromatography-tandem mass spectrometry. Western blot and staining probes showed that TMAO-induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress, and nuclear factor-κB (NF-κB) activation in vitro. Notably, the TMAO-mediated effects were reversed by the use of ER stress, mitochondrial stress, and NF-κB activation inhibitors and small interfering RNA. Mice treated with supplemental choline in a high-fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (an inhibitor of trimethylamine formation) treatment. CONCLUSIONS: Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo.

Nanomechanical Resonators: Toward Atomic Scale.

The quest for realizing and manipulating ever smaller man-made movable structures and dynamical machines has spurred tremendous endeavors, led to important discoveries, and inspired researchers to venture to previously unexplored grounds. Scientific feats and technological milestones of miniaturization of mechanical structures have been widely accomplished by advances in machining and sculpturing ever shrinking features out of bulk materials such as silicon. With the flourishing multidisciplinary field of low-dimensional nanomaterials, including one-dimensional (1D) nanowires/nanotubes and two-dimensional (2D) atomic layers such as graphene/phosphorene, growing interests and sustained effort have been devoted to creating mechanical devices toward the ultimate limit of miniaturization─genuinely down to the molecular or even atomic scale. These ultrasmall movable structures, particularly nanomechanical resonators that exploit the vibratory motion in these 1D and 2D nano-to-atomic-scale structures, offer exceptional device-level attributes, such as ultralow mass, ultrawide frequency tuning range, broad dynamic range, and ultralow power consumption, thus holding strong promises for both fundamental studies and engineering applications. In this Review, we offer a comprehensive overview and summary of this vibrant field, present the state-of-the-art devices and evaluate their specifications and performance, outline important achievements, and postulate future directions for studying these miniscule yet intriguing molecular-scale machines.