An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice.

Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders

Controlled Anisotropic Deformation of Ag Nanoparticles by Si Ion Irradiation

The shape and alignment of silver nanoparticles embedded in a glass matrix is controlled using silicon ion irradiation. Symmetric silver nanoparticles are transformed into anisotropic particles whose larger axis is along the ion beam. Upon irradiation, the surface plasmon resonance of symmetric particles splits into two resonances whose separation depends on the fluence of the ion irradiation. Simulations of the optical absorbance show that the anisotropy is caused by the deformation and alignment of the nanoparticles, and that both properties are controlled with the irradiation fluence.Comment: Submitted to Phys. Rev. Lett. (October 14, 2005

Tunable Nanometer Electrode Gaps by MeV Ion Irradiation

We report the use of MeV ion-irradiation-induced plastic deformation of amorphous materials to fabricate electrodes with nanometer-sized gaps. Plastic deformation of the amorphous metal $\text{Pd}_{80}\text{Si}_{20}$ is induced by $4.64 \text{MeV O}^{2+}$ ion irradiation, allowing the complete closing of a sub-micrometer gap. We measure the evolving gap size in situ by monitoring the field emission current-voltage (I-V) characteristics between electrodes. The I-V behavior is consistent with Fowler-Nordheim tunneling. We show that using feedback control on this signal permits gap size fabrication with atomic-scale precision. We expect this approach to nanogap fabrication will enable the practical realization of single molecule controlled devices and sensors.Engineering and Applied SciencesPhysic

Epicardial myocardial strain abnormalities may identify the earliest stages of arrhythmogenic cardiomyopathy.

The aim of this cohort study was to evaluate the value of echocardiographic multilayer strain analysis in the identification of arrhythmogenic cardiomyopathy (AC) in its earliest stages in which sudden cardiac death can occurs. Twenty seven asymptomatic relatives of AC probands (mean age 39.6 ± 19.5 years, 37 % male) with a desmosomal pathogenic mutation but no additional criteria for AC (group II) were compared to age and sex-matched healthy controls (group I). In addition, 70 patients harboring a pathogenic desmosomal mutation with "definitive" diagnosis of AC (group IV), and 19 subjects with "borderline" diagnosis (group III) were also studied. A standard echocardiographic evaluation plus left (LV) and right ventricular global and regional transmural, endocardial, and epicardial longitudinal strain (LS) analysis, was performed. In group II, while LV ejection fraction, fractional shortening, and S' were not significantly reduced compared to controls, transmural global LS was significantly reduced to 19.3 ± 1.8 % in group II versus 20.9 ± 1.1 % in controls (p = 0.0003). Compared to controls, group II presented significant (p < 0.05) regional LS decrease in the basal infero-lateral, antero-lateral, latero-apical, infero-septal, and septo-apical segments. Moreover, LS of the latero-apical and the basal antero-lateral segments was significantly altered in the epicardium (p < 0.05) but not significantly in the endocardium. Global and regional LV LS analysis allows detection of AC in an early or non-diagnostic stage of the disease. Moreover, epicardial LS analysis allows the detection of abnormalities earlier than endocardial LS

Simulation-based analysis of micro-robots swimming at the center and near the wall of circular mini-channels

Swimming micro robots have great potential in biomedical applications such as targeted drug delivery, medical diagnosis, and destroying blood clots in arteries. Inspired by swimming micro organisms, micro robots can move in biofluids with helical tails attached to their bodies. In order to design and navigate micro robots, hydrodynamic characteristics of the flow field must be understood well. This work presents computational fluid dynamics (CFD) modeling and analysis of the flow due to the motion of micro robots that consist of magnetic heads and helical tails inside fluid-filled channels akin to bodily conduits; special emphasis is on the effects of the radial position of the robot. Time-averaged velocities, forces, torques, and efficiency of the micro robots placed in the channels are analyzed as functions of rotation frequency, helical pitch (wavelength) and helical radius (amplitude) of the tail. Results indicate that robots move faster and more efficiently near the wall than at the center of the channel. Forces acting on micro robots are asymmetrical due to the chirality of the robot’s tail and its motion. Moreover, robots placed near the wall have a different flow pattern around the head when compared to in-center and unbounded swimmers. According to simulation results, time-averaged for-ward velocity of the robot agrees well with the experimental values measured previously for a robot with almost the same dimensions

Lifting Micro-Update Models from RTL for Formal Security Analysis

Hardware execution attacks exploit subtle microarchitectural interactions to leak secret data. While checking programs for the existence of such attacks is essential, verification of software against the full hardware implementation does not scale. Verification using abstract formal models of the hardware can help provide strong security guarantees while leveraging abstraction to achieve scalability. However, handwriting accurate abstract models is tedious and error-prone. Hence, we need techniques to generate models that enable sound yet scalable security analysis automatically.In this work, we propose micro-update models as a modelling framework that enables sound and abstract modelling of microarchitectural features. We also develop algorithms to generate micro-update models from RTL semi-automatically. We implement our modelling and generation framework in a prototype tool called PAUL. We evaluate our approach by synthesizing micro-update models for the Sodor5Stage processor and components from the cva6 (Ariane) processor. We demonstrate how these models can be generated hierarchically, thus increasing scalability to larger designs. We observe up to 8× improvement in run time when performing analysis with the generated models as compared to the source RTL

Synthesis in Uclid5

We describe an integration of program synthesis into Uclid5, a formal modelling and verification tool. To the best of our knowledge, the new version of Uclid5 is the only tool that supports program synthesis with bounded model checking, k-induction, sequential program verification, and hyperproperty verification. We use the integration to generate 25 program synthesis benchmarks with simple, known solutions that are out of reach of current synthesis engines, and we release the benchmarks to the community

Characterization of MTAP gene expression in breast cancer patients and cell lines

MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors\ub4 MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNB