Oligo(aryleneethynylene)s with Terminal Pyridyl Groups: Synthesis and Length Dependence of the Tunneling-to-Hopping Transition of Single-Molecule Conductances

The synthesis is reported of a new series of oligo(aryleneethynylene) (OAE) derivatives of up to ca. 6 nm in molecular length (OAE9) using iterative Pd-mediated Sonogashira cross-coupling methodology. The oligo-p-phenyleneethynylene cores of the molecular wires are functionalized at both termini with pyridyl units for attachment to gold leads. The molecular structures determined by single-crystal X-ray analysis are reported for OAE4, OAE5, OAE7, and OAE8a. The charge transport characteristics of derivatives OAE3–OAE9 in single-molecular junctions have been studied using the mechanically controlled break junction technique. The data demonstrate that the junction conductance decreases with increasing molecular length. A transition from coherent transport via tunneling to a hopping mechanism is found for OAE wires longer than ca. 3 nm.

The role of chance events in the school-to-work transition: The influence of demographic, personality and career development variables

Chance events are considered important in career development, yet little empirical research is available on their predictors and consequences. The present study investigated socio-demographic (gender, nationality, school-type), personality (openness, locus of control) and career development variables (career decidedness, career planning) in relation to perceived chance events with a retrospective (N = 229, eleventh grade), and 1-year longitudinal prospective study (N = 245, eighth/ninth grade) among Swiss adolescents. The results showed that the majority of both groups reported a significant influence of chance events on their transition from compulsory school to vocational education or high school. Importance of chance events related to socio-demographics and personality but not career preparation. Career preparation and chance events predicted subjective career success in terms of wish correspondence and overall satisfaction with transition outcome among the younger cohort. Implications include the necessity to integrate both thorough career preparation and chance events in theory and counseling practice.

Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer.

Anticancer therapies currently used in the clinic often can neither eradicate the tumor nor prevent disease recurrence due to tumor resistance. In this study, we showed that chemoresistance to pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with a stem cell-like phenotype characterized by an enriched stem cell gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, chemoresistance to MTA requires activation of epithelial-to-mesenchymal transition (EMT) pathway in that an experimentally induced EMT per se promotes chemoresistance in NSCLC and inhibition of EMT signaling by kaempferol renders the otherwise chemoresistant cancer cells susceptible to MTA. Relevant to the clinical setting, human primary NSCLC cells with an elevated EMT signaling feature a significantly enhanced potential to resist MTA, whereas concomitant administration of kaempferol abrogates MTA chemoresistance, regardless of whether it is due to an intrinsic or induced activation of the EMT pathway. Collectively, our findings reveal that a bona fide activation of EMT pathway is required and sufficient for chemoresistance to MTA and that kaempferol potently regresses this chemotherapy refractory phenotype, highlighting the potential of EMT pathway inhibition to enhance chemotherapeutic response of lung cancer.

E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell–cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for E-cadherin in ovarian neoplastic progression.

Lifetimes of intermediates in the β-sheet to α-helix transition of β-lactoglobulin by using a diffusional IR mixer

The extremely slow α-helix/β-sheet transition of proteins is a crucial step in amylogenic diseases and represents an internal rearrangement of local contacts in an already folded protein. These internal structural rearrangements within an already folded protein are a critical aspect of biological action and are a product of conformational flow along unknown metastable local minima of the energy landscape of the compact protein. We use a diffusional IR mixer with time-resolved Fourier transform IR spectroscopy capable of 400-μs time resolution to show that the trifluoroethanol driven β-sheet to α-helix transition of β-lactoglobulin proceeds via a compact β-sheet intermediate with a lifetime of 7 ms, small compared with the overall folding time of β-lactoglobulin.

Pollen abundances, and temperature and precipitation reconstruction for the Eocene to Oligocene transition in northern high latitudes

A profound global climate shift took place at the Eocene-Oligocene transition (~33.5 million years ago) when Cretaceous/early Palaeogene greenhouse conditions gave way to icehouse conditions (Zachos et al., 2001, doi:10.1126/science.1059412; Coxall et al., 2005, doi:10.1038/nature03135; Lear et al., 2008, doi:10.1130/G24584A.1). During this interval, changes in the Earth's orbit and a long-term drop in atmospheric carbon dioxide concentrations (Pagani et al., 2005, doi:10.1126/science.1110063; Pearson and Palmer, 2000, doi:10.1038/35021000; DeConto and Pollard, 2003, doi:10.1038/nature01290) resulted in both the growth of Antarctic ice sheets to approximately their modern size (Coxall et al., 2005, doi:10.1038/nature03135; Lear et al., 2008, doi:10.1130/G24584A.1) and the appearance of Northern Hemisphere glacial ice (Eldrett et al., 2007, doi:10.1038/nature05591; Moran et al., 2006, doi:10.1038/nature04800). However, palaeoclimatic studies of this interval are contradictory: although some analyses indicate no major climatic changes (Kohn et al., 2004, doi:10.1130/G20442.1; Grimes et al., 2005, doi:10.1130/G21019.1), others imply cooler temperatures (Zanazzi et al., 2007, doi:10.1038/nature05551), increased seasonality (Ivany et al., 2000, doi:10.1038/35038044; Terry, 2001, doi:10.1016/S0031-0182(00)00248-0) and/or aridity (Ivany et al., 2000, doi:10.1038/35038044; Terry, 2001, doi:10.1016/S0031-0182(00)00248-0; Sheldon et al., 2002, doi:10.1086/342865; Dupont-Nivet et al., 2007, doi:10.1038/nature05516). Climatic conditions in high northern latitudes over this interval are particularly poorly known. Here we present northern high-latitude terrestrial climate estimates for the Eocene to Oligocene interval, based on bioclimatic analysis of terrestrially derived spore and pollen assemblages preserved in marine sediments from the Norwegian-Greenland Sea. Our data indicate a cooling of ~5 °C in cold-month (winter) mean temperatures to 0-2 °C, and a concomitant increased seasonality before the Oi-1 glaciation event. These data indicate that a cooling component is indeed incorporated in the d18O isotope shift across the Eocene-Oligocene transition. However, the relatively warm summer temperatures at that time mean that continental ice on East Greenland was probably restricted to alpine outlet glaciers.

Light scattering study of human serum albumin in pre-denaturation:relation to dynamic transition in water at 42°C

Protein functional motions are ultimately connected to water dynamics. The goal of this study is to link the conformational dynamics of albumin to a dynamic transition taking place at ∼ 42°C in water. We report the results of dynamic light scattering measurements of albumin aqueous solution in the temperature interval 20-65°C. The processing of the experimental data produced the temperature dependence of the macromolecular hydrodynamic radius. We demonstrate that the growth of the macromolecular size in this temperature range can be divided into two stages that are connected to the dynamical properties of water. © 2012 Elsevier B.V. All rights reserved.

CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett’s Esophagus Malignant Progression

Barrett's esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett's malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett's progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett's samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett's esophagus neoplastic progression.

Flavonols mediate root phototropism and growth through regulation of proliferation-to-differentiation transition.

Roots normally grow in darkness, but they may be exposed to light. After perceiving light, roots bend to escape from light (root light avoidance) and reduce their growth. How root light avoidance responses are regulated is not well understood. Here, we show that illumination induces the accumulation of flavonols in Arabidopsis thaliana roots. During root illumination, flavonols rapidly accumulate at the side closer to light in the transition zone. This accumulation promotes asymmetrical cell elongation and causes differential growth between the two sides, leading to root bending. Furthermore, roots illuminated for a long period of time accumulate high levels of flavonols. This high flavonol content decreases both auxin signaling and PLETHORA gradient as well as superoxide radical content, resulting in reduction of cell proliferation. In addition, cytokinin and hydrogen peroxide, which promote root differentiation, induce flavonol accumulation in the root transition zone. As an outcome of prolonged light exposure and flavonol accumulation, root growth is reduced and a different root developmental zonation is established. Finally, we observed that these differentiation-related pathways are required for root light avoidance. We propose that flavonols function as positional signals, integrating hormonal and ROS pathways to regulate root growth direction and rate in response to light.