\u3cem\u3eIn Situ\u3c/em\u3e Nanomechanical Testing in Focused Ion Beam and Scanning Electron Microscopes

The recent interest in size-dependent deformation of micro- and nanoscale materials has paralleled both technological miniaturization and advancements in imaging and small-scale mechanical testing methods. Here we describe a quantitative in situ nanomechanical testing approach adapted to a dualbeam focused ion beam and scanning electron microscope. A transducer based on a three-plate capacitor system is used for high-fidelity force and displacement measurements. Specimen manipulation, transfer, and alignment are performed using a manipulator, independently controlled positioners, and the focused ion beam. Gripping of specimens is achieved using electron-beam assisted Pt-organic deposition. Local strain measurements are obtained using digital image correlation of electron images taken during testing. Examples showing results for tensile testing of single-crystalline metallic nanowires and compression of nanoporous Au pillars will be presented in the context of size effects on mechanical behavior and highlight some of the challenges of conducting nanomechanical testing in vacuum environments

Almost Ideal Clocks in Quantum Cosmology: A Brief Derivation of Time

A formalism for quantizing time reparametrization invariant dynamics is considered and applied to systems which contain an `almost ideal clock.' Previously, this formalism was successfully applied to the Bianchi models and, while it contains no fundamental notion of `time' or `evolution,' the approach does contain a notion of correlations. Using correlations with the almost ideal clock to introduce a notion of time, the work below derives the complete formalism of external time quantum mechanics. The limit of an ideal clock is found to be closely associated with the Klein-Gordon inner product and the Newton-Wigner formalism and, in addition, this limit is shown to fail for a clock that measures metric-defined proper time near a singularity in Bianchi models.Comment: 16 pages ReVTeX (35 preprint pages

Perfect weddings abroad

Approximately 16% of UK couples are currently married abroad. However, academic or practitioner focused research that explores the complex nature of a couple’s buying preferences or the development of innovative marketing strategies by businesses operating within the weddings abroad niche sector, is almost non-existent. This exploratory paper examines the role and relevance of marketing within the weddings abroad sector. The complex nature of customer needs in this high emotional and involvement experience, are identified and explored. A case study of Perfect Weddings Abroad Ltd highlights distinctive features and characteristics. Social networking and the use of home-workers, with a focus on reassurance and handholding are important tools used to develop relationships with customers. These tools and techniques help increase the tangibility of a weddings abroad package. Clusters of complementary services that are synergistic and provide sources of competitive advantage are identified and an agenda for future research is developed

Hydrology in the Sea of Marmara during the last 23 ka : implications for timing of Black Sea connections and sapropel deposition

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 25 (2010): PA1205, doi:10.1029/2009PA001735.Sediments deposited under lacustrine and marine conditions in the Sea of Marmara hold a Late Quaternary record for water exchange between the Black Sea and the Mediterranean Sea. Here we report a multiproxy data set based on oxygen and strontium isotope results obtained from carbonate shells, major and trace elements, and specific organic biomarker measurements, as well as a micropaleontological study from a 14C-dated sediment core retrieved from the Sea of Marmara. Pronounced changes occurred in δ18O and 87Sr/86Sr values at the fresh and marine water transition, providing additional information in relation to micropaleontological data. Organic biomarker concentrations documented the marine origin of the sapropelic layer while changes in n-alkane concentrations clearly indicated an enhanced contribution for organic matter of terrestrial origin before and after the event. When compared with the Black Sea record, the results suggest that the Black Sea was outflowing to the Sea of Marmara from the Last Glacial Maximum until the warmer Bølling-Allerød. The first marine incursion in the Sea of Marmara occurred at 14.7 cal ka B.P. However, salinification of the basin was gradual, indicating that Black Sea freshwaters were still contributing to the Marmara seawater budget. After the Younger Dryas (which is associated with a high input of organic matter of terrestrial origin) both basins were disconnected, resulting in a salinity increase in the Sea of Marmara. The deposition of organic-rich sapropel that followed was mainly related to enhanced primary productivity characterized by a reorganization of the phytoplankton population.We acknowledge support from INSU and the French Polar Institute IPEV

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What’s to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment

Triad representation of the Chern-Simons state in quantum gravity

We investigate a triad representation of the Chern-Simons state of quantum gravity with a non-vanishing cosmological constant. It is shown that the Chern-Simons state, which is a well-known exact wavefunctional within the Ashtekar theory, can be transformed to the real triad representation by means of a suitably generalized Fourier transformation, yielding a complex integral representation for the corresponding state in the triad variables. It is found that topologically inequivalent choices for the complex integration contour give rise to linearly independent wavefunctionals in the triad representation, which all arise from the one Chern-Simons state in the Ashtekar variables. For a suitable choice of the normalization factor, these states turn out to be gauge-invariant under arbitrary, even topologically non-trivial gauge-transformations. Explicit analytical expressions for the wavefunctionals in the triad representation can be obtained in several interesting asymptotic parameter regimes, and the associated semiclassical 4-geometries are discussed. In restriction to Bianchi-type homogeneous 3-metrics, we compare our results with earlier discussions of homogeneous cosmological models. Moreover, we define an inner product on the Hilbert space of quantum gravity, and choose a natural gauge-condition fixing the time-gauge. With respect to this particular inner product, the Chern-Simons state of quantum gravity turns out to be a non-normalizable wavefunctional.Comment: Latex, 30 pages, 1 figure, to appear in Phys. Rev.

An Abrupt Drowning of the Black Sea Shelf at 7.5 KYR BP

During latest Quaternary glaciation, the Black Sea became a giant freshwater lake. The surface of this lake drew down to levels more than 100m below its outlet. When the Mediterranean rose to the Bosporus sill at 7.5 kyr BP, saltwater poured through this spillway to refill the and submerge in less than a year, more than 100,000km2 of its exposed continental shelf

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Ubiquitin-specific protease 6 (USP6) is a deubiquitylase that is overexpressed by chromosome translocation in two human neoplasms, aneurysmal bone cyst and nodular fasciitis. The relevant substrates of this ubiquitin-specific protease are not clear. Here, we identify the Wnt receptor Frizzled (Fzd) as a key target of the USP6 oncogene. Increased expression of USP6 increases the membrane abundance of Fzd, and hence increases cellular sensitivity to Wnts. USP6 opposes the activity of the ubiquitin ligase and tumor suppressor ring finger protein 43 (RNF43). This study identifies a new mechanism for pathological Wnt pathway activation in human disease and suggests a new approach to regulate Wnt activity therapeutically

Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min

In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease. Copyright