Liver-specific mitochondrial amidoxime-reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models.

BACKGROUND: Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear. METHODS: Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques. RESULTS: In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet. CONCLUSIONS: Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.

Green- and Blue-Emitting Tb3+-Activated Linde Type A Zeolite-Derived Boro-Aluminosilicate Glass for Deep UV Detection/Imaging.

Tb3+-activated LTA zeolite-derived boro-aluminosilicate glass samples with a composition of xTb2O3-68(Na2O-Al2O3-SiO2)-32B2O3 (x = 0.2, 1.0 and 10 extra wt%) were prepared using the melt-quenching method. The emission spectra recorded upon ultraviolet (UV) excitation with two different wavelengths of 193 and 378 nm showed blue light (5D3 to 7FJ=6,5,4 and 5D4 to 7F6 transitions of Tb3+) and green light (5D4 to 7F5 transition of Tb3+) emissions with comparable intensities up to a Tb3+ concentration of 10 extra wt%. Of note, the mean decay times of the green luminescence of the glass samples were relatively fast (<20 µs). The synthesized glass has potential in applications concerning UV imaging, UV detection, and plasma display panels.

Electric Field Switching of Magnon Spin Current in a Compensated Ferrimagnet.

Manipulation of directional magnon propagation, known as magnon spin current, is essential for developing magnonic devices featuring nonvolatile functionalities and ultralow power consumption. Magnon spin current can usually be modulated by magnetic field or current-induced spin torques. However, these approaches may lead to energy dissipation due to Joule heating. Electric-field switching of magnon spin current without charge current is highly preferred but challenging to realize. By integrating magnonic and piezoelectric materials, the manipulation of the magnon spin current generated by the spin Seebeck effect in the ferrimagnetic insulator Gd3Fe5O12 (GdIG) film on a piezoelectric substrate is demonstrated. Reversible electric-field switching of magnon polarization without applied charge current is observed. Through strain-mediated magnetoelectric coupling, the electric field induces the magnetic compensation transition between two magnetic states of the GdIG, resulting in its magnetization reversal and the simultaneous switching of magnon spin current. This work establishes a prototype material platform that paves the way for developing magnon logic devices characterized by all electric field reading and writing and reveals the underlying physics principles of their functions.

Rapid Detection of Trace Nitro-Explosives under UV Irradiation by Electronic Nose with Neural Networks.

The development of an electronic nose (E-nose) for rapid explosive trace detection (ETD) has been extensively studied. However, the extremely low saturated vapor pressure of explosives becomes the major obstacle for E-nose to be applied in practical environments. In this work, we innovatively combine the decomposition characteristics of nitro explosives when exposed to ultraviolet light into gas sensors for detecting explosives, and an E-nose consisting of a SnO2/WO3 nanocomposite-based chemiresistive sensor array with an artificial neural network is utilized to identify trace nitro-explosives by detecting their photolysis gas products, rather than the explosive molecules themselves or their saturated vapor. The ultralow detection limits for nitro-explosives can be achieved, and the detection limits toward three representative nitro-explosives of trinitrotoluene, pentaerythritol tetranitrate, and cyclotetramethylene tetranitroamine are as low as 500, 100, and 50 ng, respectively. Moreover, by extracting the features of sensor responses within 15 s, a classification system based on convolutional neural network (CNN) and long short-term memory network (LSTM) is introduced to realize fast and accurate classification. The 5-fold cross-validation results demonstrate that the CNN-LSTM model exhibits the highest classification accuracy of 97.7% compared with those of common classification models. This work realizes the detection of explosives photolysis gases using sensor technology, which provides a unique insight for the classification of trace explosives.

Simultaneous detection of four pesticides in agricultural products by a modified QuEChERS method and LC-MS/MS.

A modified QuEChERS pretreatment method and LC-MS/MS technique were performed to simultaneously determine four pesticide (Hexachlorophene, Dinex, Dinosam, Dinoterb) residues in agricultural products. Through the optimization of LC-MS/MS detection parameters in SIM mode, the optimal instrument conditions are obtained. The modified QuEChERS method was used to pretreat the samples. Solid phase extractants PSA, C18 and GCB were used for sample purification. The research results showed that the correlation coefficients of the four pesticides were all greater than 0.991, which had a good linear relationship. The limits of quantitation (LOQ) of the four pesticides were 0.05-0.56 µg/kg. The recoveries were 70.51-113.20% with relative standard deviations (RSDS) of 1.6-11.2%. The developed method can provide reliable data support for the subsequent simultaneous detection of these four pesticides.

Highly Sensitive and Selective Surface Acoustic Wave Ammonia Sensor Operated at Room Temperature with a Polyacrylic Acid Sensing Layer.

In this study, polyacrylic acid (PAA) films were deposited onto a quartz surface acoustic wave (SAW) resonator using a spin-coating technique for ammonia sensing operated at room temperature, and the sensing mechanisms and performance were systematically studied. The oxygen-containing functional groups on the surfaces of the PAA film make it sensitive and selective to ammonia molecules, even when tested at room temperature. The ammonia molecules adsorbed by the oxygen-containing functional groups of PAA (e.g., hydroxyl and epoxy groups) increase the membrane's stiffness, which was identified as the primary mechanism leading to the positive frequency shifts. However, mass loading due to adsorption of ammonia molecules is not a major reason as it will result in a negative frequency shifts. When the PAA coated SAW sensor was exposed to ammonia with a low concentration of 500 ppb, it showed a positive frequency shift of 225 Hz, with both good repeatability and stability, as well as a good selectivity to ammonia compared with those to C2H5OH, H2, HCl, H2S, CO, NO2, NO, and CH3COCH3.

The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation.

Estrogen-related receptors (ERR) α and γ were shown recently to serve as regulators of cardiac maturation, yet the underlying mechanisms have not been delineated. Herein, we find that ERR signaling is necessary for induction of genes involved in mitochondrial and cardiac-specific contractile processes during human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) differentiation. Genomic interrogation studies demonstrate that ERRγ occupies many cardiomyocyte enhancers/super-enhancers, often co-localizing with the cardiogenic factor GATA4. ERRγ interacts with GATA4 to cooperatively activate transcription of targets involved in cardiomyocyte-specific processes such as contractile function, whereas ERRγ-mediated control of metabolic genes occurs independent of GATA4. Both mechanisms require the transcriptional coregulator PGC-1α. A disease-causing GATA4 mutation is shown to diminish PGC-1α/ERR/GATA4 cooperativity and expression of ERR target genes are downregulated in human heart failure samples suggesting that dysregulation of this circuitry may contribute to congenital and acquired forms of heart failure.

Cardiomyocyte Homeodomain-Interacting Protein Kinase 2 Maintains Basal Cardiac Function via Extracellular Signal-Regulated Kinase Signaling.

BACKGROUND: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we used an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. METHODS: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte (CM)-specific HIPK2 knockout and heterozygous mice. Heart function was examined by echocardiography, and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) was administrated to rescue cardiac dysfunction in CM-HIPK2 knockout mice. RESULTS: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in CMs leads to cardiac dysfunction, suggesting a causal role in heart failure. It is important to note that cardiac dysfunction in HIPK2 knockout mice developed with advancing age, but not during development. In addition, CM-HIPK2 knockout mice and CM-HIPK2 heterozygous mice exhibited a gene dose-response relationship of CM-HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy in comparison to nonfailing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular CMscorroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired extracellular signal-regulated kinase 1/2 signaling in HIPK2-deficient hearts. An in vivo rescue experiment with adeno-associated virus serotype 9 TnT-MEK1-CA nearly abolished the detrimental phenotype of knockout mice, suggesting that impaired extracellular signal-regulated kinase signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-HIPK2 knockout mice hearts. CONCLUSIONS: Taken together, these findings suggest that CM-HIPK2 is required to maintain normal cardiac function via extracellular signal-regulated kinase signaling.

Cardiomyocyte SMAD4-Dependent TGF-ß Signaling is Essential to Maintain Adult Heart Homeostasis.

The role of the transforming growth factor (TGF)-ß pathway in myocardial fibrosis is well recognized. However, the precise role of this signaling axis in cardiomyocyte (CM) biology is not defined. In TGF-ß signaling, SMAD4 acts as the central intracellular mediator. To investigate the role of TGF-ß signaling in CM biology, the authors deleted SMAD4 in adult mouse CMs. We demonstrate that CM-SMAD4-dependent TGF-ß signaling is critical for maintaining cardiac function, sarcomere kinetics, ion-channel gene expression, and cardiomyocyte survival. Thus, our findings raise a significant concern regarding the therapeutic approaches that rely on systemic inhibition of the TGF-ß pathway for the management of myocardial fibrosis.

Inhibition of GSK-3 to induce cardiomyocyte proliferation: a recipe for in situ cardiac regeneration.

With an estimated 38 million current patients, heart failure (HF) is a leading cause of morbidity and mortality worldwide. Although the aetiology differs, HF is largely a disease of cardiomyocyte (CM) death or dysfunction. Due to the famously limited amount of regenerative capacity of the myocardium, the only viable option for advanced HF patients is cardiac transplantation; however, donor's hearts are in very short supply. Thus, novel regenerative strategies are urgently needed to reconstitute the injured hearts. Emerging data from our lab and others have elucidated that CM-specific deletion of glycogen synthase kinase (GSK)-3 family of kinases induces CM proliferation, and the degree of proliferation is amplified in the setting of cardiac stress. If this proliferation is sufficiently robust, one could induce meaningful regeneration without the need for delivering exogenous cells to the injured myocardium (i.e. cardiac regeneration in situ). Herein, we will discuss the emerging role of the GSK-3s in CM proliferation and differentiation, including their potential implications in cardiac regeneration. The underlying molecular interactions and cross-talk among signalling pathways will be discussed. We will also review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to stimulate the endogenous cardiac regenerative responses to repair the injured heart.

Using 3D finite element models verified the importance of callus material and microstructure in biomechanics restoration during bone defect repair.

BACKGROUND: There is lack of further observations on the microstructure and material property of callus during bone defect healing and the relationships between callus properties and the mechanical strength. METHODS: Femur bone defect model was created in rabbits and harvested CT data to reconstruct finite element models at 1 and 2 months. Three types of assumed finite element models were compared to study the callus properties, which assumed the material elastic property as heterogeneous (R-model), homogenous (H-model) or did not change from 1 to 2 months (U-model). RESULTS:  The apparent elastic moduli increased at 2 months (from 355.58 ± 132.67 to 1139.30 ± 967.43 MPa) in R-models. But there was no significant difference in apparent elastic moduli between R-models (355.58 ± 132.67 and 1139.30 ± 967.43 MPa) and H-models (344.79 ± 138.73 and 1001.52 ± 692.12 MPa) in 1 and 2 months. A significant difference of apparent elastic moduli was found between the R-model (1139.30 ± 967.43 MPa) and U-model group (207.15 ± 64.60 MPa) in 2 months. CONCLUSIONS: This study showed that the callus structure stability remodeled overtime to achieve a more effective structure, while the material quality of callus tissue is a very important factor for callus strength. At the meantime, this study showed an evidence that the material heterogeneity maybe not as important as it is in bone fracture model.

Entanglement of GSK-3ß, ß-catenin and TGF-ß1 signaling network to regulate myocardial fibrosis.

Nearly every form of the heart disease is associated with myocardial fibrosis, which is characterized by the accumulation of activated cardiac fibroblasts (CFs) and excess deposition of extracellular matrix (ECM). Although, CFs are the primary mediators of myocardial fibrosis in a diseased heart, in the traditional view, activated CFs (myofibroblasts) and resulting fibrosis were simply considered the secondary consequence of the disease, not the cause. Recent studies from our lab and others have challenged this concept by demonstrating that fibroblast activation and fibrosis are not simply the secondary consequence of a diseased heart, but are crucial for mediating various myocardial disease processes. In regards to the mechanism, the vast majority of literature is focused on the direct role of canonical SMAD-2/3-mediated TGF-ß signaling to govern the fibrogenic process. Herein, we will discuss the emerging role of the GSK-3ß, ß-catenin and TGF-ß1-SMAD-3 signaling network as a critical regulator of myocardial fibrosis in the diseased heart. The underlying molecular interactions and cross-talk among signaling pathways will be discussed. We will primarily focus on recent in vivo reports demonstrating that CF-specific genetic manipulation can lead to aberrant myocardial fibrosis and sturdy cardiac phenotype. This will allow for a better understanding of the driving role of CFs in the myocardial disease process. We will also review the specificity and limitations of the currently available genetic tools used to study myocardial fibrosis and its associated mechanisms. A better understanding of the GSK-3ß, ß-catenin and SMAD-3 signaling network may provide a novel therapeutic target for the management of myocardial fibrosis in the diseased heart.

Room-Temperature Ammonia Sensor Based on ZnO Nanorods Deposited on ST-Cut Quartz Surface Acoustic Wave Devices.

Using a seed layer-free hydrothermal method, ZnO nanorods (NRs) were deposited on ST-cut quartz surface acoustic wave (SAW) devices for ammonia sensing at room temperature. For a comparison, a ZnO film layer with a thickness of 30 nm was also coated onto an ST-cut quartz SAW device using a sol-gel and spin-coating technique. The ammonia sensing results showed that the sensitivity, repeatability and stability of the ZnO NR-coated SAW device were superior to those of the ZnO film-coated SAW device due to the large surface-to-volume ratio of the ZnO NRs.

Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress.

BACKGROUND: The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti-inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl-tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. METHODS AND RESULTS: Consistent with its ability to inhibit prolyl-tRNA synthetase, halofuginone elicited a general control nonderepressible 2-dependent activation of the AAR pathway in cardiac fibroblasts as evidenced by activation of known AAR target genes, broad regulation of the transcriptome and proteome, and reversal by l-proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin II/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the AAR pathway in the heart, improved survival, pulmonary congestion, left ventricle remodeling/fibrosis, and left ventricular function, and rescued ischemic myocardium. In human cardiac fibroblasts, halofuginone profoundly reduced collagen deposition in a general control nonderepressible 2-dependent manner and suppressed the extracellular matrix proteome. In human induced pluripotent stem cell-derived cardiomyocytes, halofuginone blocked gene expression associated with endothelin-1-mediated activation of pathologic hypertrophy and restored autophagy in a general control nonderepressible 2/eIF2α-dependent manner. CONCLUSIONS: Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy.

RATIONALE: Cardiac myocyte-specific deletion of either glycogen synthase kinase (GSK)-3α and GSK-3ß leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration because of the fact that all GSK-3-targeted drugs, including the drugs already in clinical trial target both isoforms of GSK-3, and none are isoform specific. OBJECTIVE: To identify the consequences of combined deletion of cardiac myocyte GSK-3α and GSK-3ß in heart function. METHODS AND RESULTS: We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, double-knockout hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. Double-knockout cardiac myocytes showed cell cycle progression resulting in increased DNA content and multinucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe-induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. CONCLUSIONS: Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.

Highly sensitive room-temperature surface acoustic wave (SAW) ammonia sensors based on Co3O4/SiO2 composite films.

Surface acoustic wave (SAW) sensors based on Co3O4/SiO2 composite sensing films for ammonia detection were investigated at room temperature. The Co3O4/SiO2 composite films were deposited onto ST-cut quartz SAW resonators by a sol-gel method. SEM and AFM characterizations showed that the films had porous structures. The existence of SiO2 was found to enhance the ammonia sensing property of the sensor significantly. The sensor based on a Co3O4/SiO2 composite film, with 50% Co3O4 loading, which had the highest RMS value (3.72), showed the best sensing property. It exhibited a positive frequency shift of 3500 Hz to 1 ppm ammonia as well as excellent selectivity, stability and reproducibility at room temperature. Moreover, a 37% decrease in the conductance of the composite film as well as a positive frequency shift of 12,500 Hz were observed when the sensor was exposed to 20 ppm ammonia, indicating the positive frequency shift was derived from the decrease in film conductance.

Cardiac fibroblast glycogen synthase kinase-3ß regulates ventricular remodeling and dysfunction in ischemic heart.

BACKGROUND: Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed. METHODS AND RESULTS: Herein we report that glycogen synthase kinase-3ß (GSK-3ß) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3ß knockout mouse models, we show that deletion of GSK-3ß in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3ß induces a profibrotic myofibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3ß. Mechanistically, GSK-3ß inhibits profibrotic transforming growth factor-ß1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3ß resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling. CONCLUSIONS: These studies support targeting GSK-3ß in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction.

In vivo evaluation of novel amine-terminated nanopore Ti surfaces.

The aim of this study was to evaluate the effects of the novel nanopore Ti surface and amine-terminated Ti surface on peri-implant bone formation and bone-implant bonding strength in a rabbit tibiae model. Characterization of the modified Ti surface, such as root-mean square roughness, contact angle, and surface energy was evaluated using scanning electron microscopy, atomic force microscopy, and a Contact Angle Measurement System, respectively. The results from alkali treatment indicated that an interpenetrating dimensional porosity surface had been formed, whose morphology was similar to the amine-terminated surface of self-assembled monolayers after alkali treatment. The micro-CT demonstrated that the amine-terminated surface had higher bone volume ratio and higher mean trabecular thickness after 4 weeks of implantation. The push-out test and histological examination showed no significant differences in the maximal force and bone-implant contact between the terminated surface and alkali-treated surface. These novel dimensional nanoporous structures can significantly improve the initial stabilization and the osseointegration.

[The design and experiment of complementary S coding matrix based on digital micromirror spectrometer].

The template selection is essential in the application of digital micromirror spectrometer. The best theoretical coding H-matrix is not widely used due to acyclic, complex coding and difficult achievement. The noise ratio of best practical S-matrix for improvement is slightly inferior to matrix H. So we designed a new type complementary S-matrix. Through studying its noise improvement theory, the algorithm is proved to have the advantages of both H-matrix and S-matrix. The experiments proved that the SNR can be increased 2.05 times than S-template.

[Micro Hadamard transform near-infrared spectrometer].

A new type micro Hadamard transform (HT) near-infrared (NIR) spectrometer is proposed in the present paper. It has a MOEMS (Micro-Opto-Electro-Mechanical Systems) blazed grating HT mask. It has merits of compactness, agility of dynamic mask generation and high scan speed. The structure and theory of this spectrometer are analyzed. The 63-order Hadamard-S matrix and mask are designed. The mask is dynamically generated by program of MOEMS blazed gratings. The spectrum is in agreement with that measured by Shimadzu spectrometer in experiments. It has a wavelength range between 900 and 1 700 nm, spectral resolution of 19 nm, single scan time of 2.4 s, SNR of 44.67:1, optical path of 70 mm x 130 mm, and weight under 1 kg. It can meet the requirement of real time detection and portable application.