A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells

AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5′-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5′-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development

Distinguishing Lead and Molecule States in Graphene-Based Single-Electron Transistors

Graphene provides a two-dimensional platform for contacting individual molecules, which enables transport spectroscopy of molecular orbital, spin, and vibrational states. Here we report single-electron tunneling through a molecule that has been anchored to two graphene leads. Quantum interference within the graphene leads gives rise to an energy-dependent transmission and fluctuations in the sequential tunnel-rates. The lead states are electrostatically tuned by a global back-gate, resulting in a distinct pattern of varying intensity in the measured conductance maps. This pattern could potentially obscure transport features that are intrinsic to the molecule under investigation. Using ensemble averaged magneto-conductance measurements, lead and molecule states are disentangled, enabling spectroscopic investigation of the single molecule

Invited talk - Nanoscale thermal transport and unconventional thermoelectric phenomena in 2D materials

With 2D materials such as graphene (GR) and hexagonal boron nitride possessing highest known thermal conductivities, one-atom thick nature of these materials makes thermal transport in them drastically dependent on the local environment. Moreover, the equally extraordinary electronic properties of GR such as relativistic carrier dynamics combined with GR highly anisotropic thermal conductance may point to unusual thermoelectric properties. In order to study thermal and thermoelectric phenomena in these nanoscale materials, we applied scanning thermal microscopy (SThM) that uses a sharp tip in contact with the probed surface that can create a controlled local sample temperature rise in the few nm acros spot, while measuring the resulting sample temperature and a heat flow. We used high vacuum environment that eliminates spurious heat dissipation channels to boost accuracy and sensitivity and to allow cryogenic measurements. We show that the thermal resistance of GR on SiO2 is increased by one order of magnitude by the addition of a top layer of MoS2, over the temperature range 150- 300 K with DFT calculations attributing this increase to the phonon transport filtering in the weak vdW coupling and vibrational mismatch between dissimilar 2D materials. By measuring the heat generated in the nanoscale constrictions in monolayer GR devices, we have discovered unconventional thermoelectric Peltier effect due to geometrical shape of 2D material and not requiring a junction of dissimilar materials, with phenomenon confirmed by measuring the Seebeck thermovoltage map due to local heating by the SThM tip. The novel nonlinear thermoelectric phenomena due to “electron wind”, and effects of GR doping and layer number are also reported

Field-effect control of graphene–fullerene thermoelectric nanodevices

Although it was demonstrated that discrete molecular levels determine the sign and mag nitude of the thermoelectric effect in single-molecule junctions, full electrostatic control of these levels has not been achieved to date. Here, we show that graphene nanogaps combined with gold micro-heaters serve as a testbed for studying single-molecule their moelectricity. Reduced screening of the gate electric field compared to conventional metal electrodes allows controlling the position of the dominant transport orbital by hundreds of meV. We find that the power factor of graphene-fullerene junctions can be tuned over several orders of magnitude to a value close to the theoretical limit of an isolated Breit-Wigner resonance. Furthermore our data suggests that the power factor of isolated level is only given by the tunnel coupling to the leads and temperature. These results open up new avenues for exploring thermoelectricity and charge transport in individual molecules, and highlight the importance of level-alignment and coupling to the electrodes for optimum energy-conversion in organic thermoelectric materials

Seasonal changes in adipokines, fat utilization, and regulation of food intake in grizzly bears (Ursus arctos horribilis)

Many hibernating species have evolved physiological adaptations not found in more active organisms, including the ability to amass enormous adipose deposits. In humans, large amounts of adipose tissue are associated with the onset of metabolic diseases. However, in hibernating grizzly bears (Ursus arctos horribilis), obese animals are not only healthy, they are more reproductively fit than their leaner counterparts. Because we hypothesized that adipokines might reflect adiposity, we determined the annual serum profiles of leptin and adiponectin relative to body fat content. Both adipokines were present at relatively low levels throughout the active season but peaked in mid-October just prior to hibernation. Neither strongly correlated with body fat content throughout the year. Since leptin is an appetite suppressant in other animals, we tested the ability of centrally administered leptin to alter food intake at the beginning (August) and end (October) of the annual hyperphagic period. Bears treated with leptin in October significantly reduced their food intake whereas in August intake was unchanged, suggesting that the brain's sensitivity to leptin varies seasonally. We also cultured adipocytes from the active season and from hibernation under a variety of conditions to measure changes in gene expression and cellular lipolytic ability. Following treatment with bear serum collected at different times of year, leptin and its receptor responded differentially to catecholaminergic stimulation. The expression of genes closely related to lipolysis was significantly higher in hibernation cells, revealing cell autonomous changes. Taken together, the results reveal both cell-specific and systemic seasonal changes in bear adipose physiology

Правда коммунизма. 1986. № 013

Graphene is an ideal material for fabricating atomically thin nanometre spaced electrodes. Recently, carbon-based nanoelectrodes have been employed to create single-molecule transistors and phase change memory devices. In spite of the significant recent interest in their use in a range of nanoscale devices from phase change memories to molecular electronics, the operating and scaling limits of these electrodes are completely unknown. In this paper, we report on our observations of consistent voltage driven resistance switching in sub-5 nm graphene nanogaps. We find that we are able to reversibly cycle between a low and a high resistance state using feedback-controlled voltage ramps.We attribute this unexplained switching in the gap to the formation and breakdown of carbon filaments.By increasing the gap, we find that such intrinsic resistance switching of graphene nanogaps imposes a scaling limit of 10 nm (approx.) on the gap-size for devices with operating voltages of 1 to 2 volts