Preparation and Properties of Mechanically Robust, Colorless, and Transparent Aramid Films.

In this study, various diamine monomers were used to synthesize aramid polymer films via a low-temperature solution condensation reaction with diacid chloride. For diamines with relatively high basicity, the reaction system became opaque because amine salt formation inhibited polymer synthesis. Meanwhile, low-basicity diamines with strong electron-withdrawing groups, such as CF3 and sulfone, were smoothly polymerized without amine salt formation to provide highly viscous solutions. The acid byproduct HCl generated during polymerization was removed by adding propylene oxide to the reaction vessel and converting the acid into highly volatile inert substances. The resulting solutions were used as varnishes without any additional purification, and polymer films with an excellent appearance were easily obtained through a conventional casting and convection drying process. The films neither tore nor broke when pulled or bent by hand; furthermore, even when heated up to 400 °C, they did not decompose or melt. Moreover, polymers prepared from 2,2-bis(trifluoromethyl)benzidine (TFMB) and bis(4-aminophenyl)sulfone (pAPS) did not exhibit glass transition until decomposition. The prepared polymer films showed a high elastic modulus of more than 4.1 GPa and a high tensile strength of more than 52 MPa. In particular, TFMB-, pAPS-, and 2,2-bis(4-aminophenyl)hexafluoropropane-based polymer films were colorless and transparent, with very high light transmittances of 95%, 96%, and 91%, respectively, at 420 nm and low yellow indexes of 2.4, 1.9, and 4.3, respectively.

Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome.

Downregulation of endothelial Sirtuin1 (Sirt1) in insulin resistant states contributes to vascular dysfunction. Furthermore, Sirt1 deficiency in skeletal myocytes promotes insulin resistance. Here, we show that deletion of endothelial Sirt1, while impairing endothelial function, paradoxically improves skeletal muscle insulin sensitivity. Compared to wild-type mice, male mice lacking endothelial Sirt1 (E-Sirt1-KO) preferentially utilize glucose over fat, and have higher insulin sensitivity, glucose uptake, and Akt signaling in fast-twitch skeletal muscle. Enhanced insulin sensitivity of E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation. Endothelial Sirt1 deficiency, by inhibiting autophagy and activating nuclear factor-kappa B signaling, augments expression and secretion of thymosin beta-4 (Tß4) that promotes insulin signaling in skeletal myotubes. Thus, unlike in skeletal myocytes, Sirt1 deficiency in the endothelium promotes glucose homeostasis by stimulating skeletal muscle insulin sensitivity through a blood-borne mechanism, and augmented secretion of Tß4 by Sirt1-deficient endothelial cells boosts insulin signaling in skeletal muscle cells.

SUMOylation of the cardiac sodium channel NaV1.5 modifies inward current and cardiac excitability.

BACKGROUND: Decreased peak sodium current (INa) and increased late sodium current (INa,L), through the cardiac sodium channel NaV1.5 encoded by SCN5A, cause arrhythmias. Many NaV1.5 posttranslational modifications have been reported. A recent report concluded that acute hypoxia increases INa,L by increasing a small ubiquitin-like modifier (SUMOylation) at K442-NaV1.5. OBJECTIVE: The purpose of this study was to determine whether and by what mechanisms SUMOylation alters INa, INa,L, and cardiac electrophysiology. METHODS: SUMOylation of NaV1.5 was detected by immunoprecipitation and immunoblotting. INa was measured by patch clamp with/without SUMO1 overexpression in HEK293 cells expressing wild-type (WT) or K442R-NaV1.5 and in neonatal rat cardiac myocytes (NRCMs). SUMOylation effects were studied in vivo by electrocardiograms and ambulatory telemetry using Scn5a heterozygous knockout (SCN5A+/-) mice and the de-SUMOylating protein SENP2 (AAV9-SENP2), AAV9-SUMO1, or the SUMOylation inhibitor anacardic acid. NaV1.5 trafficking was detected by immunofluorescence. RESULTS: NaV1.5 was SUMOylated in HEK293 cells, NRCMs, and human heart tissue. HyperSUMOylation at NaV1.5-K442 increased INa in NRCMs and in HEK cells overexpressing WT but not K442R-Nav1.5. SUMOylation did not alter other channel properties including INa,L. AAV9-SENP2 or anacardic acid decreased INa, prolonged QRS duration, and produced heart block and arrhythmias in SCN5A+/- mice, whereas AAV9-SUMO1 increased INa and shortened QRS duration. SUMO1 overexpression enhanced membrane localization of NaV1.5. CONCLUSION: SUMOylation of K442-Nav1.5 increases peak INa without changing INa,L, at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in INa,L. Nav1.5 SUMOylation may modify arrhythmic risk in disease states and represents a potential target for pharmacologic manipulation.

Role of miR-204 in segmental cardiac effects of phenylephrine and pressure overload.

Cardiotoxicity caused by adrenergic receptor agonists overdosing or stress-induced catecholamine release promotes cardiomyopathy, resembling Takotsubo cardiomyopathy (TC). TC is characterized by transient regional systolic dysfunction of the left ventricle. The animal models of TC and modalities for assessing regional wall motion abnormalities in animal models are lacking. We previously reported the protective role of a small noncoding microRNA-204-5p (miR-204) in cardiomyopathies, but its role in TC remains unknown. Here we compared the impact of miR-204 absence on phenylephrine (PE)-induced and transaortic constriction (TAC)-induced changes in cardiac muscle motion in the posterior and anterior apical, mid, and basal segments of the left ventricle using 2-dimensional speckle-tracking echocardiography (2-STE). Wildtype and miR-204-/- mice were subjected to cardiac stress in the form of PE for four weeks or TAC-induced pressure overload for five weeks. PE treatment increased longitudinal and radial motion in the apex of the left ventricle and shortened the peak motion time of all left ventricle segments. The TAC led to decreased longitudinal and radial motion in the left ventricle segments, and there was no difference in the peak motion time. Compared to wildtype mice, PE-induced peak cardiac muscle motion time in the anterior base of the left ventricle was significantly earlier in the miR-204-/- mice. There was no difference in TAC-induced peak cardiac muscle motion time between wildtype and miR-204-/- mice. Our findings demonstrate that PE and TAC induce regional wall motion abnormalities that 2-STE can detect. It also highlights the role of miR-204 in regulating cardiac muscle motion during catecholamine-induced cardiotoxicity.

Epipericardial Fat Necrosis in a Pediatric Patient Diagnosed Using Contrast-Enhanced MRI Findings: A Case Report and Literature Review.

Epipericardial fat necrosis (EPFN) is a relatively rare cause of acute chest pain, with only five pediatric cases having been reported in the English-language medical literature to date. EPFN can be diagnosed based on the clinical symptoms of acute pleuritic chest pain and classic CT features of typically ovoid fatty lesions surrounded by a rim or capsule in the mediastinal or pericardial areas. Previous studies have reported that contrast-enhanced MRI can detect typical fat signal changes in adults with EPFN. We report a pediatric EPFN case diagnosed using gadolinium-enhanced MRI. Thus, contrast-enhanced MRI may be used to confirm EPFN in the differential diagnoses of the causes of acute chest pain.

miR204 potentially promotes non-alcoholic fatty liver disease by inhibition of cpt1a in mouse hepatocytes.

Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic metabolism dysfunction. However, the mechanistic role of miR204 in the development of NAFLD is unknown. We investigate the functional significance of miR204 in the evolution of NAFLD. IDH2 KO mice feed a normal diet (ND) or HFD increased body weight, epididymal fat-pad weight, lipid droplet in liver, blood parameter and inflammation compared to WT mice fed a ND or HFD. Moreover, the expression of miR204 is increased in mice with IDH2 deficiency. Increased miR204 by IDH2 deficiency regulates carnitine palmitoyltransferase 1a (cpt1a) synthesis, which inhibits fatty acid ß-oxidation. Inhibition of miR204 prevents the disassembly of two fatty acid-related genes by activating CPT1a expression, which decreases lipid droplet in liver, inflammatory cytokines, epididymal fat pad weight, blood parameters. Increased miR204 by IDH2 deficiency promotes the pathogenesis of HFD-induced NAFLD by regulating hepatic fatty acid metabolism and inflammation.

γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet.

The blood levels of microRNA-122 (miR-122) is associated with the severity of cardiovascular disorders, and targeting it with efficient and safer miR inhibitors could be a promising approach. Here, we report the generation of a γ-peptide nucleic acid (γPNA)-based miR-122 inhibitor (γP-122-I) that rescues vascular endothelial dysfunction in mice fed a high-fat diet. We synthesized diethylene glycol-containing γP-122-I and found that its systemic administration counteracted high-fat diet (HFD)-feeding-associated increase in blood and aortic miR-122 levels, impaired endothelial function, and reduced glycemic control. A comprehensive safety analysis established that γP-122-I affects neither the complete blood count nor biochemical tests of liver and kidney functions during acute exposure. In addition, long-term exposure to γP-122-I did not change the overall adiposity, or histology of the kidney, liver, and heart. Thus, γP-122-I rescues endothelial dysfunction without any evidence of toxicity in vivo and demonstrates the suitability of γPNA technology in generating efficient and safer miR inhibitors.

The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.

BACKGROUND: MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA-204-5p (miR-204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood. METHODS: We performed RNA-sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR-204 five weeks after trans-aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR-204. RESULTS: The stretch induces miR-204 expression, and miR-204 inhibits the stretch-induced hypertrophic response of H9C2 cells. The mice lacking miR-204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno-associated virus serotype-9-mediated cardioselective miR-204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR-204 knockout mice following pressure overload suggested deregulation of apelin-receptor (APJ) signalling. We found that the stretch-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation and hypertrophy-related genes expression depend on the APJ, and both of these effects are subject to miR-204 levels. The dynamin inhibitor dynasore inhibited both stretch-induced APJ endocytosis and ERK1/2 activation. In contrast, the miR-204-induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR-204 increases the expression of ras-associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis. CONCLUSIONS: Our results show that miR-204 regulates trafficking of APJ and confers resistance to pressure overload-induced CH/CD, and boosting miR-204 can inhibit the development of CH/CD.

Atrial-paced, exercise-similar heart rate envelope induces myocardial protection from ischaemic injury.

AIMS: The study investigates the role and mechanisms of clinically translatable exercise heart rate (HR) envelope effects, without dyssynchrony, on myocardial ischaemia tolerance compared to standard preconditioning methods. Since the magnitude and duration of exercise HR acceleration are tightly correlated with beneficial cardiac outcomes, it is hypothesized that a paced exercise-similar HR envelope, delivered in a maximally physiologic way that avoids the toxic effects of chamber dyssynchrony, may be more than simply a readout, but rather also a significant trigger of myocardial conditioning and stress resistance. METHODS AND RESULTS: For 8 days over 2 weeks, sedated mice were atrial-paced once daily via an oesophageal electrode to deliver an exercise-similar HR pattern with preserved atrioventricular and interventricular synchrony. Effects on cardiac calcium handling, protein expression/modification, and tolerance to ischaemia-reperfusion (IR) injury were assessed and compared to those in sham-paced mice and to the effects of exercise and ischaemic preconditioning (IPC). The paced cohort displayed improved myocardial IR injury tolerance vs. sham controls with an effect size similar to that afforded by treadmill exercise or IPC. Hearts from paced mice displayed changes in Ca2+ handling, coupled with changes in phosphorylation of calcium/calmodulin protein kinase II, phospholamban and ryanodine receptor channel, and transcriptional remodelling associated with a cardioprotective paradigm. CONCLUSIONS: The HR pattern of exercise, delivered by atrial pacing that preserves intracardiac synchrony, induces cardiac conditioning and enhances ischaemic stress resistance. This identifies the HR pattern as a signal for conditioning and suggests the potential to repurpose atrial pacing for cardioprotection.

One-Step Synthesis of NbSe2/Nb-Doped-WSe2 Metal/Doped-Semiconductor van der Waals Heterostructures for Doping Controlled Ohmic Contact.

van der Waals heterostructures (vdWHs) of metallic (m-) and semiconducting (s-) transition-metal dichalcogenides (TMDs) exhibit an ideal metal/semiconductor (M/S) contact in a field-effect transistor. However, in the current two-step chemical vapor deposition process, the synthesis of m-TMD on pregrown s-TMD contaminates the van der Waals (vdW) interface and hinders the doping of s-TMD. Here, NbSe2/Nb-doped-WSe2 metal-doped-semiconductor (M/d-S) vdWHs are created via a one-step synthesis approach using a niobium molar ratio-controlled solution-phase precursor. The one-step growth approach synthesizes Nb-doped WSe2 with a controllable doping concentration and metal/doped-semiconductor vdWHs. The hole carrier concentration can be precisely controlled by controlling the Nb/(W + Nb) molar ratio in the precursor solution from ∼3 × 1011/cm2 at Nb-0% to ∼1.38 × 1012/cm2 at Nb-60%; correspondingly, the contact resistance RC value decreases from 10 888.78 at Nb-0% to 70.60 kΩ.µm at Nb-60%. The Schottky barrier height measurement in the Arrhenius plots of ln(Isat/T2) versus q/KBT demonstrated an ohmic contact in the NbSe2/WxNb1-xSe2 vdWHs. Combining p-doping in WSe2 and M/d-S vdWHs, the mobility (27.24 cm2 V-1 s-1) and on/off ratio (2.2 × 107) are increased 1238 and 4400 times, respectively, compared to that using the Cr/pure-WSe2 contact (0.022 cm2 V-1 s-1 and 5 × 103, respectively). Together, the RC value using the NbSe2 contact shows 2.46 kΩ.µm, which is ∼29 times lower than that of using a metal contact. This method is expected to guide the synthesis of various M/d-S vdWHs and applications in future high-performance integrated circuits.

Selective Pattern Growth of Atomically Thin MoSe2 Films via a Surface-Mediated Liquid-Phase Promoter.

Two-dimensional transition metal dichalcogenides (TMDs) offer numerous advantages over silicon-based application in terms of atomically thin geometry, excellent opto-electrical properties, layer-number dependence, band gap variability, and lack of dangling bonds. The production of high-quality and large-scale TMD films is required with consideration of practical technology. However, the performance of scalable devices is affected by problems such as contamination and patterning arising from device processing; this is followed by an etching step, which normally damages the TMD film. Herein, we report the direct growth of MoSe2 films on selective pattern areas via a surface-mediated liquid-phase promoter using a solution-based approach. Our growth process utilizes the promoter on the selective pattern area by enhancing wettability, resulting in a highly uniform MoSe2 film. Moreover, our approach can produce other TMD films such as WSe2 films as well as control various pattern shapes, sizes, and large-scale areas, thus improving their applicability in various devices in the future. Our patterned MoSe2 field-effect transistor device exhibits a p-type dominant conduction behavior with a high on/off current ratio of ∼106. Thus, our study provides general guidance for direct selective pattern growth via a solution-based approach and the future design of integrated devices for a large-scale application.

Genetic deletion of miR-204 improves glycemic control despite obesity in db/db mice.

MicroRNAs (miRs) are small non-coding RNAs that regulate the target gene expression. A change in miR profile in the pancreatic islets during diabetes is known, and multiple studies have demonstrated that miRs influence the pancreatic ß-cell function. The miR-204 is highly expressed in the ß-cells and reported to regulate insulin synthesis. Here we investigated whether the absence of miR-204 rescues the impaired glycemic control and obesity in the genetically diabetic (db/db) mice. We found that the db/db mice overexpressed miR-204 in the islets. The db/db mice lacking miR-204 (db/db-204-/-) initially develops hyperglycemia and obesity like the control (db/db) mice but later displayed a gradual improvement in glycemic control despite remaining obese. The db/db-204-/- mice had a lower fasting blood glucose and higher serum insulin level compared to the db/db mice. A homeostatic model assessment (HOMA) suggests the improvement of ß-cell function contributes to the improvement in glycemic control in db/db-204-/- mice. Next, we examined the cellular proliferation and endoplasmic reticulum (ER) stress and found an increased frequency of proliferating cells (PCNA + ve) and a decreased CHOP expression in the islets of db/db-204-/- mice. Next, we determined the effect of systemic miR-204 inhibition in improving glycemic control in the high-fat diet (HFD)-fed insulin-resistant mice. MiR-204 inhibition for 6 weeks improved the HFD-triggered impairment in glucose disposal. In conclusion, the absence of miR-204 improves ß-cell proliferation, decreases islet ER stress, and improves glycemic control with limited change in body weight in obese mice.

Microbiota-governed microRNA-204 impairs endothelial function and blood pressure decline during inactivity in db/db mice.

An impaired decline in blood pressure at rest is typical in people with diabetes, reflects endothelial dysfunction, and increases the risk of end-organ damage. Here we report that microRNA-204 (miR-204) promotes endothelial dysfunction and impairment in blood pressure decline during inactivity. We show that db/db mice overexpress miR-204 in the aorta, and its absence rescues endothelial dysfunction and impaired blood pressure decline during inactivity despite obesity. The vascular miR-204 is sensitive to microbiota, and microbial suppression reversibly decreases aortic miR-204 and improves endothelial function, while the endothelial function of mice lacking miR-204 remained indifferent to the microbial alterations. We also show that the circulating miR-122 regulates vascular miR-204 as miR-122 inhibition decreases miR-204 in endothelial cells and aorta. This study establishes that miR-204 impairs endothelial function, promotes impairment in blood pressure decline during rest, and opens avenues for miR-204 inhibition strategies against vascular dysfunction.

Photoinduced Tuning of Schottky Barrier Height in Graphene/MoS2 Heterojunction for Ultrahigh Performance Short Channel Phototransistor.

Two-dimensional (2D) layered materials with properties such as a large surface-to-volume ratio, strong light interaction, and transparency are expected to be used in future optoelectronic applications. Many studies have focused on ways to increase absorption of 2D-layered materials for use in photodetectors. In this work, we demonstrate another strategy for improving photodetector performance using a graphene/MoS2 heterojunction phototransistor with a short channel length and a tunable Schottky barrier. The channel length of sub-30 nm, shorter than the diffusion length, decreases carrier recombination and carrier transit time in the channel and improves phototransistor performance. Furthermore, our graphene/MoS2 heterojunction phototransistor employed a tunable Schottky barrier that is only controlled by light and gate bias. It maintains a low dark current and an increased photocurrent. As a result, our graphene/MoS2 heterojunction phototransistor showed ultrahigh responsivity and detectivity of 2.2 × 105 A/W and 3.5 × 1013 Jones, respectively. This is a considerable improvement compared to previous pristine MoS2 phototransistors. We confirmed an effective method to develop phototransistors based on 2D materials and obtained ultrahigh performance of our phototransistor, which is promising for high-performance optoelectronic applications.

Unveiling the Hot Carrier Distribution in Vertical Graphene/h-BN/Au van der Waals Heterostructures for High-Performance Photodetector.

Graphene is one of the most promising materials for photodetectors due to its ability to convert photons into hot carriers within approximately 50 fs and generate long-lived thermalized states with lifetimes longer than 1 ps. In this study, we demonstrate a wide range of vertical photodetectors having a graphene/h-BN/Au heterostructure in which an hexagonal boron nitride (h-BN) insulating layer is inserted between an Au electrode and graphene photoabsorber. The photocarriers effectively tunnel through the small hole barrier (1.93 eV) at the Au/h-BN junction while the dark carriers are highly suppressed by a large electron barrier (2.27 eV) at the graphene/h-BN junction. Thus, an extremely low dark current of ∼10-13 A is achieved, which is 8 orders of magnitude lower than that of graphene lateral photodetector devices (∼10-5 A). Also, our device displays an asymmetric photoresponse behavior due to photothermionic emission at the graphene/h-BN and Au/h-BN junctions. The asymmetric behavior generates additional thermal carriers (hot carriers) to enable our device to generate photocurrents that can overcome the Schottky barrier. Furthermore, our device shows the highest value of the Iph/Idark ratio of ∼225 at 7 nm thick h-BN insulating layer, which is 3 orders of magnitude larger than that of the previously reported graphene lateral photodetectors without any active materials. In addition, we achieve a fast response speed of 12 µs of rise time and 5 µs of fall time, which are about 100 times faster than those of other graphene integrated photodetectors.

SUMO2 regulates vascular endothelial function and oxidative stress in mice.

SUMOylation is a posttranslational modification of lysine residues. Modification of proteins by small ubiquitin-like modifiers (SUMO)1, -2, and -3 can achieve varied, and often unique, physiological and pathological effects. We looked for SUMO2-specific effects on vascular endothelial function. SUMO2 expression was upregulated in the aortic endothelium of hypercholesterolemic low-density lipoprotein receptor-deficient mice and was responsible for impairment of endothelium-dependent vasorelaxation in these mice. Moreover, overexpression of SUMO2 in aortas ex vivo, in cultured endothelial cells, and transgenically in the endothelium of mice increased vascular oxidative stress and impaired endothelium-dependent vasorelaxation. Conversely, inhibition of SUMO2 impaired physiological endothelium-dependent vasorelaxation in normocholesterolemic mice. These findings indicate that while endogenous SUMO2 is important in maintenance of normal endothelium-dependent vascular function, its upregulation impairs vascular homeostasis and contributes to hypercholesterolemia-induced endothelial dysfunction.NEW & NOTEWORTHY Sumoylation is known to impair vascular function; however, the role of specific SUMOs in the regulation of vascular function is not known. Using multiple complementary approaches, we show that hyper-SUMO2ylation impairs vascular endothelial function and increases vascular oxidative stress, whereas endogenous SUMO2 is essential for maintenance of normal physiological function of the vascular endothelium.

Efficient Gate Modulation in a Screening-Engineered MoS2/Single-Walled Carbon Nanotube Network Heterojunction Vertical Field-Effect Transistor.

In this report, a screening-engineered carbon nanotube (CNT) network/MoS2/metal heterojunction vertical field effect transistor (CNT-VFET) is fabricated for an efficient gate modulation independent of the drain voltage. The gate field in the CNT-VFET transports through the empty space of the CNT network without any screening layer and directly modulates the MoS2 semiconductor energy band, while the gate field from the Si back gate is mostly screened by the graphene layer. Consequently, the on/off ratio of CNT-VFET maintained 103 in overall drain voltages, which is 10 times and 1000 times higher than that of the graphene (Gr) VFET at Vsd = 0.1 (ratio = 81.9) and 1 V (ratio = 3), respectively. An energy band diagram simulation shows that the Schottky barrier modulation of CNT/MoS2 contact along the sweeping gate bias is independent of the drain voltage. On the other hand, the gate modulation of Gr/MoS2 is considerably reduced with increased drain voltage because more electrons are drawn into the graphene electrode and screens the gate field by applying a higher drain voltage to the graphene/MoS2/metal capacitor.

Ultrahigh Gauge Factor in Graphene/MoS2 Heterojunction Field Effect Transistor with Variable Schottky Barrier.

Piezoelectricity of transition metal dichalcogenides (TMDs) under mechanical strain has been theoretically and experimentally studied. Powerful strain sensors using Schottky barrier variation in TMD/metal junctions as a result of the strain-induced lattice distortion and associated ion-charge polarization were demonstrated. However, the nearly fixed work function of metal electrodes limits the variation range of a Schottky barrier. We demonstrate a highly sensitive strain sensor using a variable Schottky barrier in a MoS2/graphene heterostructure field effect transistor (FET). The low density of states near the Dirac point in graphene allows large modulation of the graphene Fermi level and corresponding Schottky barrier in a MoS2/graphene junction by strain-induced polarized charges of MoS2. Our theoretical simulations and temperature-dependent electrical measurements show that the Schottky barrier change is maximized by placing the Fermi level of the graphene at the charge neutral (Dirac) point by applying gate voltage. As a result, the maximum Schottky barrier change (ΔΦSB) and corresponding current change ratio under 0.17% strain reach 118 meV and 978, respectively, resulting in an ultrahigh gauge factor of 575 294, which is approximately 500 times higher than that of metal/TMD junction strain sensors (1160) and 140 times higher than the conventional strain sensors (4036). The ultrahigh sensitivity of graphene/MoS2 heterostructure FETs can be developed for next-generation electronic and mechanical-electronic devices.

MiR-204 regulates type 1 IP3R to control vascular smooth muscle cell contractility and blood pressure.

MiR-204 is expressed in vascular smooth muscle cells (VSMC). However, its role in VSMC contraction is not known. We determined if miR-204 controls VSMC contractility and blood pressure through regulation of sarcoplasmic reticulum (SR) calcium (Ca2+) release. Systolic blood pressure (SBP) and vasoreactivity to VSMC contractile agonists (phenylephrine (PE), thromboxane analogue (U46619), endothelin-1 (ET-1), angiotensin-II (Ang II) and norepinephrine (NE) were compared in aortas and mesenteric resistance arteries (MRA) from miR-204-/- mice and wildtype mice (WT). There was no difference in basal systolic blood pressure (SBP) between the two genotypes; however, hypertensive response to Ang II was significantly greater in miR-204-/- mice compared to WT mice. Aortas and MRA of miR-204-/- mice had heightened contractility to all VSMC agonists. In silico algorithms predicted the type 1 Inositol 1, 4, 5-trisphosphate receptor (IP3R1) as a target of miR-204. Aortas and MRA of miR-204-/- mice had higher expression of IP3R1 compared to WT mice. Difference in agonist-induced vasoconstriction between miR-204-/- and WT mice was abolished with pharmacologic inhibition of IP3R1. Furthermore, Ang II-induced aortic IP3R1 was greater in miR-204-/- mice compared to WT mice. In addition, difference in aortic vasoconstriction to VSMC agonists between miR-204-/- and WT mice persisted after Ang II infusion. Inhibition of miR-204 in VSMC in vitro increased IP3R1, and boosted SR Ca2+ release in response to PE, while overexpression of miR-204 downregulated IP3R1. Finally, a sequence-specific nucleotide blocker that targets the miR-204-IP3R1 interaction rescued miR-204-induced downregulation of IP3R1. We conclude that miR-204 controls VSMC contractility and blood pressure through IP3R1-dependent regulation of SR calcium release.

Personalized Prediction of Acquired Resistance to EGFR-Targeted Inhibitors Using a Pathway-Based Machine Learning Approach.

Epidermal growth factor receptor (EGFR) inhibitors have benefitted cancer patients worldwide, but resistance inevitably develops over time, resulting in treatment failures. An accurate prediction model for acquired resistance (AR) to EGFR inhibitors is critical for early diagnosis and according intervention, but is not yet available due to personal variations and the complex mechanisms of AR. Here, we have developed a novel pipeline to build a meta-analysis-based, multivariate model for personalized pathways in AR to EGFR inhibitors, using sophisticated machine learning algorithms. Surprisingly, the model achieved excellent predictive performance, with a cross-study validation area under curve (AUC) of over 0.9, and generalization performance on independent cohorts of samples, with a perfect AUC score of 1. Furthermore, the model showed excellent transferability across different cancer cell lines and EGFR inhibitors, including gefitinib, erlotinib, afatinib, and cetuximab. In conclusion, our model achieved high predictive accuracy through robust cross study validation, and enabled individualized prediction on newly introduced data. We also discovered common pathway alteration signatures for AR to EGFR inhibitors, which can provide directions for other follow-up studies.