Miracle-dz/UniFAR-FTUs huggingface dataset:
MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines. MEDI-573 potently inhibited in vitro proliferation of sarcoma cell lines, with Ewing sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGFI- and IGFII-induced sarcoma cell proliferation in vitro. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGFIR, pIR-A, and pAKT and significantly blocked IGFI- and IGFII-induced activation of the IGFIR and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGFI and IGFII. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor (mTORi), significantly enhanced the antitumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by IGFI and IGFII, and inhibition of IGFI and IGFII by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing sarcoma. These data provide evidence for the potential benefits of MEDI-573 and mTORi combinations in patients with Ewing sarcoma. Mol Cancer Ther; 13(11); 2662–73. ©2014 AACR.
C-type Lectins L-SIGN and DC-SIGN Capture and Transmit Infectious Hepatitis C Virus Pseudotype Particles*

The molecular mechanisms involved in the hepatic tropism of hepatitis C virus (HCV) have not been identified. We have shown previously that liver-expressed C-type lectins L-SIGN and DC-SIGN bind the HCV E2 glycoprotein with high affinity (Lozach, P. Y., Lortat-Jacob, H., de Lacroix de Lavalette, A., Staropoli, I., Foung, S., Amara, A., Houles, C., Fieschi, F., Schwartz, O., Virelizier, J. L., Arenzana-Seisdedos, F., and Altmeyer, R. (2003) J. Biol. Chem. 278, 20358–20366). To analyze the functional relevance of this interaction, we generated pseudotyped lentivirus particles presenting HCV glycoproteins E1 and E2 at the virion surface (HCV-pp). High mannose N-glycans are present on E1 and, to a lesser extent, on E2 proteins of mature infectious HCV-pp. Such particles bind to both L-SIGN and DC-SIGN, but they cannot use these receptors for entry into cells. However, infectious virus is transmitted efficiently when permissive Huh-7 cells are cocultured with HCV-pp bound to L-SIGN or to DC-SIGN-positive cell lines. HCV-pp transmission via L-SIGN or DC-SIGN is inhibited by characteristic inhibitors such as the calcium chelator EGTA and monoclonal antibodies directed against lectin carbohydrate recognition domains of both lectins. In support of the biological relevance of this phenomenon, dendritic cells expressing endogenous DC-SIGN transmitted HCV-pp with high efficiency in a DC-SIGN-dependent manner. Our results support the hypothesis that C-type lectins such as the liver sinusoidal endothelial cell-expressed L-SIGN could act as a capture receptor for HCV in the liver and transmit infectious virions to neighboring hepatocytes.
Inconsistency of the MLE for the Joint Distribution of Interval‐Censored Survival Times and Continuous Marks

Abstract. This paper considers the non‐parametric maximum likelihood estimator (MLE) for the joint distribution function of an interval‐censored survival time and a continuous mark variable. We provide a new explicit formula for the MLE in this problem. We use this formula and the mark‐specific cumulative hazard function of Huang & Louis (1998) to obtain the almost sure limit of the MLE. This result leads to necessary and sufficient conditions for consistency of the MLE, which imply that the MLE is inconsistent in general. We show that the inconsistency can be repaired by discretizing the marks. Our theoretical results are supported by simulations.
Improved reliability characteristics of submicrometer nMOSFETs with oxynitride gate dielectric prepared by rapid thermal oxidation in N/sub 2/O

Submicrometer MOSFETs with ultrathin oxynitride gate dielectric grown in pure N/sub 2/O ambient were studied. The peak mobility of oxynitride is 5% lower than that of control oxide. However, the oxynitride shows 10% less mobility degradation under high normal field. Compared with the control oxide device, the oxynitride device shows significantly less degradation under channel hot-electron stress. The lifetime of the oxynitride device is approximately one order of magnitude longer than that of the control oxide sample. Significant improvement of device reliability is due to the nitrogen incorporation during the oxidation process. <<ETX>>
Insulin-sensitizing and Anti-proliferative Effects of Argania spinosa Seed Extracts

Argania spinosa is an evergreen tree endemic of southwestern Morocco. Many preparations have been used in traditional Moroccan medicine for centuries to treat several illnesses including diabetes. However, scientific evidence supporting these actions is lacking. Therefore, we prepared various extracts of the argan fruit, namely keel, cake and argan oil extracts, which we tested in the HTC hepatoma cell line for their potential to affect cellular insulin responses. Cell viability was measured by Trypan Blue exclusion and the response to insulin evaluated by the activation of the extracellular regulated kinase (ERK1/2), ERK kinase (MEK1/2) and protein kinase B (PKB/Akt) signaling components. None of the extracts demonstrated significant cytotoxic activity. Certain extracts demonstrated a bi-phasic effect on ERK1/2 activation; low doses of the extract slightly increased ERK1/2 activation in response to insulin, whereas higher doses completely abolished the response. In contrast, none of the extracts had any significant effect on MEK whereas only a cake saponin subfraction enhanced insulin-induced PKB/Akt activation. The specific action of argan oil extracts on ERK1/2 activation made us consider an anti-proliferative action. We have thus tested other transformed cell lines (HT-1080 and MSV-MDCK-INV cells) and found similar results. Inhibition of ERK1/2 activation was also associated with decreased DNA synthesis as evidenced by [3H]thymidine incorporation experiments. These results suggest that the products of Argania spinosa may provide a new therapeutic avenue against proliferative diseases.
Sulfated Derivatives of Escherichia coli K5 Polysaccharides as Modulators of Fibroblast Growth Factor Signaling*

Heparan sulfate (HS) proteoglycans are intimately involved in the regulation of fibroblast growth factor (FGF) signaling. HS and the related glycosaminoglycan heparin interact with FGFs and FGF receptors (FGFRs), and it is believed that both interactions are required for productive FGF signaling. Attempts to inhibit FGF activity have been made with modified heparin preparations, various heparin-like polysaccharide analogues and other polyanionic molecules, which may all act by interfering with the physiological HS-FGF-FGFR interactions on the cell surface. Here, we have studied the potential of sulfated derivatives of a bacterial polysaccharide (capsular polysaccharide from Escherichia coli K5 (K5PS)) in the modulation of FGF-heparin/HS interactions and FGF signaling. We demonstrate that O-sulfated and N,O-sulfated species of K5PS, with high degrees of sulfation, displaced FGF-1, FGF-2, and FGF-8b from heparin. However, only O-sulfated K5PS efficiently inhibited the FGF-induced proliferation of S115 mammary carcinoma cells and 3T3 fibroblasts, whereas N,O-sulfated K5PS had little or no inhibitory effect. Studies with CHO677 cells lacking endogenous HS, as well as with chlorate-treated S115 cells expressing undersulfated HS, indicated that whereas exogenously administered heparin and N,O-sulfated K5PS restored the cellular response toward FGF stimulation, O-sulfated K5PS was largely devoid of such stimulatory activity. Our data suggest that highly O-sulfated species of K5PS may be efficient inhibitors of FGF signaling.
Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution

Purpose: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs. Experimental Design: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes. Results: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007). Conclusions: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.
The influence of smartphones on academic performance: The development of the technology-to-performance chain model

Purpose The purpose of this paper is to investigate the factors that influence college students’ smartphone use for academic purposes by identifying the task-technology fit (TTF) of smartphones. A research model is proposed to explain how TTF of smartphones affects college students’ perceived academic performance and smartphone use. Design/methodology/approach Online surveys were administered to college students at a South Korean university that has offered online academic services for more than five years, and 1,923 valid responses were analyzed. The study used partial least squares path modeling to evaluate the measurement model, and the bootstrapping technique to test the significance of the hypotheses. Findings The findings highlight that the TTF of smartphones has a direct influence on students’ perceptions of performance impact and an indirect influence on smartphone use through a precursor of utilization, such as attitude toward smartphone use, social norms and facilitating conditions. Research limitations/implications Despite a reasonably large sample, a single cross-sectional survey has a likelihood of selection bias in the sample. Practical implications This study applies the TTF model to smartphone use among college students and suggests an effective way to motivate them to use mobile technologies for their academic activities. Originality/value The present study develops an empirical model to assess the adoption of smartphones and its effect on college students’ academic performance. Above all, the study identifies a causal relationship among TTF, precursor of utilization, smartphone use and a perceived impact on academic performance based on the development and validation of the TTF constructs of smartphones.
Effect of Al Substitution on Structural, Magnetic, and Magnetocaloric Properties of Er6Fe23−xAlx (x = 0 and 3) Intermetallic Compounds

The structural, magnetic, and magnetocaloric properties of Er6Fe23−xAlx (x = 0 and 3) intermetallic compounds have been studied systematically. Samples were prepared using the arc furnace by annealing at 1073 K for one week. Rietveld analysis of XRD shows the formation of pure crystalline phase with cubic Fm-3m structure. Refinement results show that the unit cell volume decreases with increasing Al content. The Curie temperature Tc of the prepared samples was found to be strongly dependent on the aluminum content. This reduces magnetization and the ferrimagnetic phase transition temperature (Tc) from 481 K (for x = 0) to 380 K (for x = 3), is due to the substitution of magnetic element (Fe) by non-magnetic atoms (Al). With the increase of the Al content, a decrease in the values of magnetic entropy is observed. The magnitude of the isothermal magnetic entropy (|∆SM|) at the Tc decreases from 1.8 J/kg·K for x = 0 to 0.58 J/kg·K for x = 3 for a field change 14 kOe. Respectively, the relative cooling power (RCP) decreases with increasing Al content reaching 42 Jkg−1 for x = 0 to 28 Jkg−1 for x = 3.
The pollination ecology of Paraboea rufescens (Gesneriaceae): a buzz-pollinated tropical herb with mirror-image flowers.

BACKGROUND AND AIMS Gesneriaceae is a pantropical plant family with over 3000 species. A great variety of pollination mechanisms have been reported for the neotropical members of the family, but the details of buzz-pollination and enantiostyly for the family have not been described. We investigated the floral biology and pollination ecology of Paraboea rufescens in Xishuangbanna, south-west China, considering three aspects: (1) the type of enantiostyly exhibited; (2) whether the species is self-compatible; and (3) whether pollinator behaviour could enhance the precision of pollen transfer between flowers of contrasting stylar orientation. METHODS Flowering phenology was monitored once a month during vegetative growth, and once a week during flowering both in the field and under cultivation. Pollination manipulations and pollinator observation in the field were conducted. KEY RESULTS Anthesis occurred early during the morning, and flowers remained open for 1-5 d, depending on weather conditions. Controlled pollinations revealed that P. rufescens is self-compatible, and exhibited inbreeding depression in seed set. Plants were pollinator limited in natural populations. The similar stylar deflection among flowers within a plant limits autonomous self-pollination as well as pollination between flowers. Two species of bumble bees (Bombus spp.), Amegila malaccensis and Nomia sp. effectively pollinated P. rufescens. These pollinators visited flowers in search of pollen with almost the same frequency. None of the pollinators appeared to discriminate between left- or right-handed flowers. CONCLUSIONS Paraboea rufescens exhibits monomorphic enantiostylous flowers and a buzz-pollination syndrome. Floral morphology in P. rufescens and pollinator foraging behaviour seems likely to reduce self-pollination and pollinations between flowers of the same stylar deflection.
The defocusing energy-critical nonlinear Schrödinger equation in higher dimensions

We obtain global well-posedness, scattering, and global $L^{\frac{2(n+2)}{n-2}}_{t,x}$ spacetime bounds for energy-space solutions to the energy-critical nonlinear Schrodinger equation in $\R_t\times \R^n_x$, $n\geq 5$.
Functional Conservation of the Yeast and Arabidopsis RAD54-Like Genes

The Saccharomyces cerevisiae RAD54 gene has critical roles in DNA double-strand break repair, homologous recombination, and gene targeting. Previous results show that the yeast gene enhances gene targeting when expressed in Arabidopsis thaliana. In this work we address the trans-species compatibility of Rad54 functions. We show that overexpression of yeast RAD54 in Arabidopsis enhances DNA damage resistance severalfold. Thus, the yeast gene is active in the Arabidopsis homologous-recombination repair system. Moreover, we have identified an A. thaliana ortholog of yeast RAD54, named AtRAD54. This gene, with close sequence similarity to RAD54, complements methylmethane sulfonate (MMS) sensitivity but not UV sensitivity or gene targeting defects of rad54Δ mutant yeast cells. Overexpression of AtRAD54 in Arabidopsis leads to enhanced resistance to DNA damage. This gene's assignment as a RAD54 ortholog is further supported by the interaction of AtRad54 with AtRad51 and the interactions between alien proteins (i.e., yeast Rad54 with AtRAD51 and yeast Rad51 with AtRad54) in a yeast two-hybrid experiment. These interactions hint at the molecular nature of this interkingdom complementation, although the stronger effect of the yeast Rad54 in plants than AtRad54 in yeast might be explained by an ability of the Rad54 protein to act alone, independently of its interaction with Rad51.
Dementia Home Care Resources: How Are We Managing?

With the number of people living with dementia expected to more than double within the next 25 years, the demand for dementia home care services will increase. In this critical ethnographic study, we drew upon interview and participant data with persons with dementia, family caregivers, in-home providers, and case managers in nine dementia care networks to examine the management of dementia home care resources. Three interrelated, dialectical themes were identified: (1) finite formal care-inexhaustible familial care, (2) accessible resources rhetoric-Iinaccessible resources reality, and (3) diminishing care resources-increasing care needs. The development of policies and practices that provide available, accessible, and appropriate resources, ensuring equitable, not necessarily equal, distribution of dementia care resources is required if we are to meet the goal of aging in place now and in the future.
An essential role for decorin in bladder cancer invasiveness

Muscle‐invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49‐I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49‐I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49‐I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49‐I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle‐invasive human bladder carcinomas, which overexpress decorin together with angiogenesis‐ and adhesion/migration‐related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.
Fault tolerant control using an admissible model matching approach

In the pseudo-inverse method (PIM) the Frobenius norm based distance between the closed loop model of the faulty system and some reference model is minimized. Stability issues are considered in the Modified PIM (MPIM). This paper proposes to use a set of admissible models, rather than searching for an optimal one which does not provide any stability / performance guarantee. The approach allows to characterize the set of recoverable faults, and to associate some robustness property with the fault adaptation scheme.
Child-Witnessed Domestic Violence and its Adverse Effects on Brain Development: A Call for Societal Self-Examination and Awareness

There is substantial evidence indicating that children who witness domestic violence (DV) have psychosocial maladaptation that is associated with demonstrable changes in the anatomic and physiological make up of their central nervous system. Individuals with these changes do not function well in society and present communities with serious medical, sociological, and economic dilemmas. In this focused perspective, we discuss the psychosocially induced biological alterations (midbrain, cerebral cortex, limbic system, corpus callosum, cerebellum, and the hypothalamic, pituitary, and adrenal axis) that are related to maladaptation (especially post-traumatic stress disorder) in the context of child-witnessed DV, and provide evidence for these physical alterations to the brain. Herein, we hope to stimulate the necessary political discourse to encourage legal systems around the world to make the act of DV in the presence of a child, including a first time act, a stand-alone felony.
Activation of group III metabotropic glutamate receptors by endogenous glutamate protects against glutamate‐mediated excitotoxicity in the hippocampus in vivo

Perfusion of 4‐aminopyridine (4‐AP) by microdialysis in the hippocampus produces intense epileptiform behavioral and electrical activity and neurodegeneration, resulting from a stimulated release of glutamate from nerve endings. In contrast, accumulation of extracellular glutamate by blockade of its transport in vivo in anesthetized rats is innocuous, and studies in vitro in brain slices suggest that under these conditions glutamate may activate presynaptic group III metabotropic glutamate receptors (mGluRs) and inhibit its own release. Therefore, using microdialysis, EEG recording, and histological evaluation, we studied the effect of increased endogenous extracellular glutamate by blockade of its transport with pyrrolidine dicarboxylic acid (PDC) on the excitotoxic action of 4‐AP in the hippocampus of awake rats. We found that up to a 20‐fold increase in extracellular glutamate during >90 min with PDC does not induce any sign of excitotoxicity. On the contrary, this glutamate increase notably protected against the 4‐AP‐induced seizures and neurodegeneration, and, remarkably, this protection was dependent on the time of perfusion with PDC and thus on the duration of extracellular glutamate accumulation. To test whether this protective action was mediated by the activation of group III mGluRs, we used specific antagonists of these receptors and found that they clearly prevented the protective effect of PDC, without affecting the accumulation of extracellular glutamate. We conclude that the spillover of the excess extracellular glutamate activates presynaptic group III mGluRs and inhibits the stimulatory effect of 4‐AP on its release, thus preventing the activation of postsynaptic N‐methyl‐D‐aspartate receptors and its deleterious consequences. © 2012 Wiley Periodicals, Inc.
Does Genotype Predict Phenotype in Rett Syndrome?

Mutations in the X-linked gene encoding the methyl-CpG binding protein MeCP2 are the primary cause of classic and atypical Rett syndrome and have recently been shown to contribute to other neurodevelopmental disorders of varying severity. To determine whether there are molecular correlates to the phenotypic heterogeneity, numerous groups have performed genotype-phenotype correlation studies. These studies have yielded conflicting results, in part because they used different criteria for determining severity and classifying mutations. Evolution of the phenotype with age and variable expressivity arising from individual variability in X-chromosome inactivation patterns are among other reasons the findings varied. Nonetheless, evidence of differences in the phenotypic consequences of specific types of mutations is emerging. This review analyzes the available literature and makes recommendations for future studies. (J Child Neurol 2005;20:768—778).