Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.

Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.

Porous and nanowire-structured NiO/AgNWs composite electrodes for significantly-enhanced supercapacitive and electrochromic performances.

NiO/AgNWs composite films which specially contain both porous and one-dimensional (1D) nanowire structures are prepared uniformly via a simple chemical bath deposition method. The supercapacitive electrodes constructed by the as-prepared NiO/AgNWs composite films exhibit a high specific capacitance (980 F g-1at 1 A g-1), much higher than that of the pure NiO films. Particularly, a large optical modulation (84.3% at 550 nm) and short switching times for the coloration and bleaching (5.4 and 6.5 s) are also observed if these NiO/AgNWs films serve as the electrochromic materials. The superior capacitive and electrochromic properties of the NiO/AgNWs composite films are attributed to the large electrochemically effective surface areas and enhanced conductivity induced by the addition of 1D AgNWs, which efficiently shorten the ions/electrons diffusion paths and accelerate the reversible redox reactions. Therefore, the NiO/AgNWs composite films hold a great potential for applications as a novel electrode material in supercapacitive and electrochromic devices.

Percolation-amplified infrared sensitivity in titanium oxide-multi-walled carbon nanotube composite films.

Titanium dioxide (TiO2)-multi-walled carbon nanotube (MWCNT) thin films were prepared and studied systematically for the effects of the concentration of MWCNTs on the electro-optical properties. Result shows that the addition of MWCNTs not only improves the optical absorption and electrical conductivity, but also reduces the 1/f noise of the films. Percolation phenomenon is observed at MWCNT concentrations of 0.20-0.25 wt%. In this concentration range, the composite films exhibit an abrupt rise of the temperature coefficient of resistance value (-2.93% K-1) and large general thermal parameter, both of which are desirable for applications in uncooled infrared detectors.

Amplified molecular detection sensitivity in passive dielectric cavity.

Vibrational absorption spectroscopy presents an effective and direct way for molecular detection and identification. In this paper, we propose and demonstrate a simple strategy and structure to amplify molecular detection sensitivity via the example of a monolayer octadecanethiol (ODT). The underlying amplification mechanism operates on both the enhanced surface field in and the coupled-oscillators' energy transfer between the molecules and the cavity underneath. The structure is designed to be simple and free of lithography or patterning with the potential for large-scale uses. It is made of just a quarter wavelength thick dielectric (ZnSe) layer atop a metallic reflecting base. Both angle and polarization dependent reflection spectra reveal signatures of CH2 and CH3 vibrations in theory and experiment. A vibrational signal intensity of 8.54% reached in s-polarization at a large incident angle is comparable to those reported in plasmonic nanostructures with greater sophistications in structure.

Wide-angle broadband absorption in tapered patch antennas.

Strip array is a classical antenna structure, which provides an effective way to generate and explore new material properties and device functionalities. In this paper, we demonstrate wide-angle broadband absorption in patch antennas made of tapered strip arrays in the metal-insulator-metal geometry. By superimposing multiple resonances associated with the tapered width of the strips, near-perfect absorption is designed and realized over a wide bandwidth from 29.2 THz to 38 THz with efficiency exceeding 80% in the mid-infrared region. The strong absorption band is insensitive to incident angles up to 75°. The angle-independent absorption is attributed to the unique mechanism of coupling between relevant magnetic resonances and free-space incident light. Our tapered patch antenna design offers the advantage of simplicity, and therefore flexibility in engineering natural materials for strong omnidirectional absorption with a variable and wide bandwidth, which could be of interest in applications such as bolometric sensing, camouflaging, and spectral filtering.

Field-controllable second harmonic generation at a graphene oxide heterointerface.

We report on the voltage-dependent SHG signal obtained in a reduced-graphene oxide (rGO)/p-type Si heterointerface. A simple qualitative model considering the interaction between the heterointerface depletion region potential and the naturally occurring surface dipole layer on the rGO is introduced to account for the characteristics of the SHG signal, specifically, a minimum point at ≈ -3 V bias on the rGO side of the interface. This feature-rich system has the potential to provide field-controllable surface-dipole moments and second-order nonlinearities, which may find applications in tunable nonlinear photonic devices for realizing second-harmonic generation and optical-rectification.

A terahertz study of taurine: Dispersion correction and mode couplings.

The low-frequency characteristics of polycrystalline taurine were studied experimentally by terahertz (THz) absorption spectroscopy and theoretically by ab initio density-functional simulations. Full optimizations with semi-empirical dispersion correction were performed in spectral computations and vibrational mode assignments. For comparison, partial optimizations with pure density functional theory were conducted in parallel. Results indicate that adding long-range dispersion correction to the standard DFT better reproduces the measured THz spectra than the popular partial optimizations. The main origins of the observed absorption features were also identified. Moreover, a coupled-oscillators model was proposed to explain the experimental observation of the unusual spectralblue-shift with the increase of temperature. Such coupled-oscillators model not only provides insights into the temperature dynamics of non-bonded interactions but also offers an opportunity to better understand the physical mechanisms behind the unusual THz spectral behaviors in taurine. Particularly, the simulation approach and novel coupled-oscillators model presented in this work are applicable to analyze the THz spectra of other molecular systems.

Wideband tunable mid-infrared cross polarization converter using rectangle-shape perforated graphene.

The strong plasmonic response and wide electrostatic tunability of graphene make it a promising material for developing infrared optoelectronic components. In this paper, we present a mid-infrared wideband tunable cross polarization converter using periodically perforated graphene. The polarization converter consists of a metal ground plane, an insulator layer, and a rectangle-shape periodically perforated graphene sheet. By superimposing two localized surface plasmon modes, the polarization converter transforms a linear polarization to its cross polarization over a bandwidth as wide as ~5% of the central frequency (46.8THz) with a peak conversion ratio exceeding 90%. The polarization conversion performance is maintained over a wide range of incident angles up to 50°, and is highly tunable by electrostatic tuning of the graphene Fermi energy. Our proposed device enables the manipulation of light polarization for potential mid-infrared applications.

Identification of a small molecule HIV-1 inhibitor that targets the capsid hexamer.

The HIV-1 CA protein is an attractive therapeutic target for the development of new antivirals. An inter-protomer pocket within the hexamer configuration of the CA, which is a binding site for key host dependency factors, is an especially appealing region for small molecule targeting. Using a field-based pharmacophore derived from an inhibitor known to interact with this region, coupled to biochemical and biological assessment, we have identified a new compound that inhibits HIV-1 infection and that targets the assembled CA hexamer.

Broadband and highly absorbing multilayer structure in mid-infrared.

In this paper, we have designed and experimentally demonstrated a broadband absorber in the mid-infrared region based on the impedance matching method. The absorber is made of planar multilayered dielectric and metallic films without involving lithography in fabrication. Our measurements reveal high absorption over 85% in the wavelength range of 2.2-6.2 µm. This wideband absorption is shown to be independent of the polarization and can be maintained over a range of incident angles up to 45°. The resultant absorber has potential applications for thermal shielding, camouflaging, sensing, etc.

Thyroglobulin antibody resolution after total thyroidectomy for cancer.

BACKGROUND: Thyroglobulin antibodies (TgAb) are produced by 10%-25% of thyroid cancer patients and interfere with thyroglobulin measurement, a marker of residual or recurrent cancer after surgery. Our purpose was to describe the TgAb resolution time course and the significance of persistent antibody elevation after thyroidectomy. METHODS: A database of 247 consecutive patients with TgAb measured preoperatively who underwent thyroidectomy for differentiated thyroid cancer between January 2007 and May 2013 was reviewed. Patients were stratified by TgAb status (positive or negative) and recurrence (defined as biopsy proven disease or unplanned second surgery). Survival and regression analysis was used to determine TgAb resolution time course. Log-rank was used to determine an association between persistent antibody elevation and recurrence. RESULTS: Of 247 patients (77% women, 23% men; mean 45.7 ± 1.0 y) with TgAb measured preoperatively, 34 (14%) were TgAb+ (≥20 IU/mL; mean 298.1 ± 99.2 IU/mL). Median time to TgAb resolution was 11.0 ± 2.3 mo, and the majority resolved by 32.4 mo. Regression analysis of patients with antibody resolution yielded an average decline of -11% IU/mL per month ± 2.2%. Disease-free survival was equivalent between TgAb-positive and TgAb-negative groups (P = 0.8). In 9 of 34 patients, antibodies had not resolved at the last follow-up and imaging could not identify recurrent disease. CONCLUSIONS: TgAb are common in patients with thyroid cancer but resolve after treatment at approximately -11% IU/mL per month from preoperative levels with median resolution at 11.0 mo. Persistently elevated levels after thyroidectomy were not associated with disease recurrence in our series.

Molecular weight effects on the phase-change-enhanced temperature coefficient of resistance in carbon nanotube/poly(N-isopropylacrylamide) composites.

We investigate the temperature coefficient of resistance (TCR), of carbon nanotube composites with the phase-change polymer poly(N-isopropylacrylamide). Our results shed light on the underlying mechanism of electron transport through networks of conductive paths in the composites and its dependence on the molecular weights (MWs) of the phase-changing polymer. Measurements of the humidity dependence of the TCR reveal the dominant conduction mechanism to be variable range hopping with an exponent of », corresponding to transport in a 3D system. In a humid atmosphere, a twenty-fold change in the hopping activation energy is observed as the temperature is swept across the polymer's hydrophilic-to-hydrophobic phase-transition, while no change is observed in low humidity atmospheres or in vacuum. The TCR was found to depend on MW but to also be affected by details of the dynamics of hydration/dehydration of the composites. For operation in dry atmospheres and in vacuum the maximum TCR observed was only .002%, while in a humid atmosphere the TCR as large as 60% were observed-an order of magnitude higher than those found in common high-TCR materials used in thermal sensing applications.

Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication.

Despite the considerable successes of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, cumulative drug toxicities and the development of multidrug-resistant virus necessitate the search for new classes of antiretroviral agents with novel modes of action. The HIV-1 capsid (CA) protein has been structurally and functionally characterized as a druggable target. We have recently designed a novel small molecule inhibitor I-XW-053 using the hybrid structure based method to block the interface between CA N-terminal domains (NTD-NTD interface) with micromolar affinity. In an effort to optimize and improve the efficacy of I-XW-053, we have developed the structure activity relationship of I-XW-053 compound series using ligand efficiency methods. Fifty-six analogues of I-XW-053 were designed that could be subclassified into four different core domains based on their ligand efficiency values computed as the ratio of binding efficiency (BEI) and surface efficiency (SEI) indices. Compound 34 belonging to subcore-3 showed an 11-fold improvement over I-XW-053 in blocking HIV-1 replication in primary human peripheral blood mononuclear cells (PBMCs). Surface plasmon resonance experiments confirmed the binding of compound 34 to purified HIV-1 CA protein. Molecular docking studies on compound 34 and I-XW-053 to HIV-1 CA protein suggested that they both bind to NTD-NTD interface region but with different binding modes, which was further validated using site-directed mutagenesis studies.

Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.

Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. SIGNIFICANCE: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.

Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics.

Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity-dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.

Trojan-horse nanotube on-command intracellular drug delivery.

A major challenge to nanomaterial-based medicine is the ability to release drugs on-command. Here, we describe an innovative drug delivery system based on carbon nanotubes (CNTs), in which compounds can be released inside cells from within the nanotube "on-command" by inductive heating with an external alternating current or pulsed magnetic field. Without inductive heating the drug remains safely inside the CNTs, showing no toxicity in cell viability tests. Similar to the "Trojan-Horse" in function, we demonstrate the delivery of a combination of chemotherapeutic agents with low aqueous solubility, paclitaxel (Taxol), and C6-ceramide, to multidrug resistant pancreatic cancer cells. Nanotube encapsulation permitted the drugs to be used at a 100-fold lower concentration compared to exogenous treatment yet achieve a comparable ~70% cancer kill rate.

Enhanced thermoelectric power in nanopatterned carbon nanotube film.

Despite the small or near-zero Seebeck coefficient of metallic nanotubes, a nanotube film can be readily scaled up in length. Thus so can its thermoelectric power. In this work, we inserted a nanomesh pattern into a carbon nanotube film by using an anodized aluminum oxide membrane as an etching mask. We found that by patterning densely packed nanoscale holes into the nanotube film, its total thermoelectric power can be further increased, by as much as 30% (from 29 to 39 µV K(-1)). We present this finding, attributed to electron localization due to nanopatterning, as indicative of the potential of a new degree of freedom.

Evaluation of metal-nanowire electrical contacts by measuring contact end resistance.

It is known, but often unappreciated, that the performance of nanowire (NW)-based electrical devices can be significantly affected by electrical contacts between electrodes and NWs, sometimes to the extent that it is really the contacts that determine the performance. To correctly understand and design NW device operation, it is thus important to carefully measure the contact resistance and evaluate the contact parameters, specific contact resistance and transfer length. A four-terminal pattern or a transmission line model (TLM) pattern has been widely used to measure contact resistance of NW devices and the TLM has been typically used to extract contact parameters of NW devices. However, the conventional method assumes that the electrical properties of semiconducting NW regions covered by a metal are not changed after electrode formation. In this study, we report that the conventional methods for contact evaluation can give rise to considerable errors because of an altered property of the NW under the electrodes. We demonstrate that more correct contact resistance can be measured from the TLM pattern rather than the four-terminal pattern and correct contact parameters including the effects of changed NW properties under electrodes can be evaluated by using the contact end resistance measurement method.

Reflectivity spectra and colors of porous anodic aluminum oxide containing silver nanoparticles by plasmonic absorption.

The reflectivity spectra and color of porous anodic aluminum oxide (AAO) nanostructures containing the assembly of silver (Ag) nanoparticles (NPs) with a diameter of -10 nm were investigated. The Ag NPs were assembled inside the pores of AAO with a diameter of -60 nm by dip-coating process during which Ag NPs adsorbed on the surface of AAO and driven inside the pores by capillary force upon the evaporation of solvent. The reflectivity spectra and associated colors of AAO with Ag NPs were determined by the plasmonic absorption of light by Ag NPs. Even with the monolayer coverage of Ag NPs in the pores of AAO, the reflectivity is significantly reduced specifically at -465 nm wavelength by a strong plasmonic absorption, resulting in its golden color. Aggregating Ag NPs by post-annealing at 300 and 400 degrees C changed the color to pink due to the red-shift of absorption. These results are indicative of potential color-engineering of NPs/AAO platform by wavelength-selective reduction of reflected light intensity and using it in direct optical read-out of change of surface and morphology conditions.