The rockefeller university

Cancers exhibiting epithelial-mesenchymal transition (EMT) are associated with aggressive behavior and increased metastatic potential. Therapies that are able to target EMT would have significant clinical value. Nectin-1 is a cell surface herpes simplex virus type 1 (HSV-1) receptor that also forms a component of intercellular adherens junctions, which are typically disrupted in EMT. To explore relationships between HSV-1 sensitivity and EMT, we generated cell lines with a stable EMT phenotype from human follicular thyroid cancer (WRO82-1) through E-cadherin silencing with short hairpin RNA (shEcadWRO). HSV-1 viral attachment and gene expression were both enhanced in shEcadWRO as compared with shControl. Immunoblotting and immunostaining revealed enhanced nectin-1 expression by shEcadWRO. Receptor-blocking assays demonstrated that increased herpesviral entry into shEcadWRO as compared with shControl was mediated predominantly through nectin-1. Colocalization of green fluorescent protein-tagged HSV-1 and tdTomato-tagged nectin-1 confirmed an increase in viral attachment to nectin-1 in shEcadWRO. Cell viability assays demonstrated increased susceptibility of shEcadWRO to HSV-1 oncolysis, and a murine flank tumor model showed significantly enhanced regression of shEcadWRO tumors in response to oncolytic HSV-1 as compared with control tumors. A separate model of EMT induction through transforming growth factor- stimulation confirmed enhanced HSV-1 susceptibility in Panc1 cells. These results demonstrate that the process of EMT leads to increased herpesviral susceptibility through enhanced cell surface nectin-1 expression, suggesting that cancers exhibiting EMT may be naturally sensitive targets for herpesviral therapy.

Immunity relies on the heterogeneity of immune cells and their ability to respond to pathogen challenges. In the adaptive immune system, lymphocytes display a highly diverse antigen receptor repertoire that matches the vast diversity of pathogens. In the innate immune system, the cell's heterogeneity and phenotypic plasticity enable flexible responses to changes in tissue homeostasis caused by infection or damage. The immune responses are calibrated by the graded activity of immune cells that can vary from yeast-like proliferation to lifetime dormancy. This article describes key epigenetic processes that contribute to the function of immune cells during health and disease.

Background: Jatropha curcas is being promoted as a new bioenergy crop in tropical and subtropical regions due to its high amount of seed oil and its potential capacity to grow on marginal land for biofuel production. However, the productivity of the plant is constrained by the unfavorable flowering time and inflorescence architecture, which render harvesting of seeds time-consuming and labor-intensive. These flowering-related traits have limited further widespread cultivation of Jatropha. Results: We identified a Jatropha curcas homolog of Flowering locus T (JcFT) and demonstrated its function by genetic complementation of the Arabidopsis ft mutant. The JcFT expression level was found to be remarkably correlated with leaf age. Overexpression of JcFT in Jatropha reduced flowering time and altered plant architecture by producing more branches. Grafting experiments suggested that the earlyflowering and alteration of plant architecture traits were graft-transmissible. We also showed that the FT-overexpressing transgenic Jatropha can be used as a root stock for grafting of scions derived from other Jatropha. Conclusion: We generated early flowering transgenic Jatropha plants that accumulate higher levels of the florigen FT. Not only early flowering but also plant growth was affected in JcFT overexpression lines. More seeds can be produced in a shorter time frame by shortening the flowering time in Jatropha, suggesting the possibility to increase seed yield by manipulating the flowering time.

Tissues rely upon stem cells for homeostasis and repair. Recent studies show that the fate and multilineage potential of epithelial stem cells can change depending on whether a stem cell exists within its resident niche and responds to normal tissue homeostasis, whether it is mobilized to repair a wound, or whether it is taken from its niche and challenged to de novo tissue morphogenesis after transplantation. In this Review, we discuss how different populations of naturally lineage-restricted stem cells and committed progenitors can display remarkable plasticity and reversibility and reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. We also discuss the implications of cellular plasticity for regenerative medicine and for cancer.

Background: Anabolic-androgenic steroids (AASs) are abused primarily in the context of intense exercise and for the purposes of increasing muscle mass as opposed to drug-induced euphoria. AASs also modulate the HPA axis and may increase the reinforcing value of exercise through changes to stress hormone and endorphin release. To test this hypothesis, 26 adult males drawn from a larger study on AAS use completed a progressive ratio task designed to examine the reinforcing value of exercise relative to financial reinforcer. Method: Sixteen experienced and current users (8 on-cycle, 8 off-cycle) and 10 controls matched on quantity x frequency of exercise, age, and education abstained from exercise for 24 h prior to testing and provided 24-h cortisol, plasma cortisol, ACTH, beta-endorphin samples, and measures of mood, compulsive exercise, and body image. Results: Between group differences indicated that on-cycle AAS users had the highest beta-endorphin levels, lowest cortisol levels, higher ACTH levels than controls. Conversely, off-cycle AAS users had the highest cortisol and ACTH levels, but the lowest beta-endorphin levels. Exercise value was positively correlated with beta-endorphin and symptoms of AAS dependence. Conclusion: The HPA response to AASs may explain why AASs are reinforcing in humans and exercise may play a key role in the development of AAS dependence. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24(+) cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/beta-catenin signaling pathway. CD24(+) cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24(+) cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24(+) cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.

We report evidence for s-channel single-top-quark production in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV using a data set that corresponds to an integrated luminosity of 9.4 fb(-1) collected by the Collider Detector at Fermilab. We select events consistent with the s-channel process including two jets and one leptonically decaying W boson. The observed significance is 3.8 standard deviations with respect to the background-only prediction. Assuming a top-quark mass of 172.5 GeV/c(2), we measure the s-channel cross section to be 1.41(-0.42)(+0.44) pb.

We present a measurement of the ZZ-boson pair-production cross section in 1.96 TeV center-of-mass energy p (p) over bar collisions. We reconstruct final states incorporating four charged leptons or two charged leptons and two neutrinos from the full data set collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.7 fb(-1) of integrated luminosity. Combining the results obtained from each final state, we measure a cross section of 1.04(-0.25)(+0.32) pb, in good agreement with the standard model prediction at next-to-leading order in the strong-interaction coupling.

It is not clear how, after a large perturbation, the brain explores the vast space of potential neuronal activity states to recover those compatible with consciousness. Here, we analyze recovery from pharmacologically induced coma to show that neuronal activity en route to consciousness is confined to a low-dimensional subspace. In this subspace, neuronal activity forms discrete metastable states persistent on the scale of minutes. The network of transitions that links these metastable states is structured such that some states form hubs that connect groups of otherwise disconnected states. Although many paths through the network are possible, to ultimately enter the activity state compatible with consciousness, the brain must first pass through these hubs in an orderly fashion. This organization of metastable states, along with dramatic dimensionality reduction, significantly simplifies the task of sampling the parameter space to recover the state consistent with wakefulness on a physiologically relevant timescale.