Evidence for a glassy state in strongly driven carbon

Here, we report results of an experiment creating a transient, highly correlated carbon state using a combination of optical and x-ray lasers. Scattered x-rays reveal a highly ordered state with an electrostatic energy significantly exceeding the thermal energy of the ions. Strong Coulomb forces are predicted to induce nucleation into a crystalline ion structure within a few picoseconds. However, we observe no evidence of such phase transition after several tens of picoseconds but strong indications for an over-correlated fluid state. The experiment suggests a much slower nucleation and points to an intermediate glassy state where the ions are frozen close to their original positions in the fluid.

A Significance-Driven Programming Framework for Energy-Constrained Approximate Computing

Approximate execution is a viable technique for energy-con\-strained environments, provided that applications have the mechanisms to produce outputs of the highest possible quality within the given energy budget.
We introduce a framework for energy-constrained execution with controlled and graceful quality loss. A simple programming model allows users to express the relative importance of computations for the quality of the end result, as well as minimum quality requirements. The significance-aware runtime system uses an application-specific analytical energy model to identify the degree of concurrency and approximation that maximizes quality while meeting user-specified energy constraints. Evaluation on a dual-socket 8-core server shows that the proposed
framework predicts the optimal configuration with high accuracy, enabling energy-constrained executions that result in significantly higher quality compared to loop perforation, a compiler approximation technique.

Incorporating PGMs into a BDI Architecture

In this paper, we present a hybrid BDI-PGM framework, in which PGMs (Probabilistic Graphical Models) are incorporated into a BDI (belief-desire-intention) architecture. This work is motivated by the need to address the scalability and noisy sensing issues in SCADA (Supervisory Control And Data Acquisition) systems. Our approach uses the incorporated PGMs to model the uncertainty reasoning and decision making processes of agents situated in a stochastic environment. In particular, we use Bayesian networks to reason about an agent’s beliefs about the environment based on its sensory observations, and select optimal plans according to the utilities of actions defined in influence diagrams. This approach takes the advantage of the scalability of the BDI architecture and the uncertainty reasoning capability of PGMs. We present a prototype of the proposed approach using a transit scenario to validate its effectiveness.

Can(Plan)+: Extending the Operational Semantics of the BDI Architecture to deal with Uncertain Information

The BDI architecture, where agents are modelled based on their beliefs, desires and intentions, provides a practical approach to develop large scale systems. However, it is not well suited to model complex Supervisory Control And Data Acquisition (SCADA) systems pervaded by uncertainty. In this paper we address this issue by extending the operational semantics of Can(Plan) into Can(Plan)+. We start by modelling the beliefs of an agent as a set of epistemic states where each state, possibly using a different representation, models part of the agent's beliefs. These epistemic states are stratified to make them commensurable and to reason about the uncertain beliefs of the agent. The syntax and semantics of a BDI agent are extended accordingly and we identify fragments with computationally efficient semantics. Finally, we examine how primitive actions are affected by uncertainty and we define an appropriate form of lookahead planning.

Three-dimensional modeling of the human fallopian tube fimbriae

OBJECTIVE: Ovarian cancer is the most lethal gynecological malignancy that affects women. Recent data suggests that the disease may originate in the fallopian fimbriae; however, the anatomical origin of ovarian carcinogenesis remains unclear. This is largely driven by our lack of knowledge regarding the structure and function of normal fimbriae and the relative paucity of models that accurately recapitulate the in vivo fallopian tube. Therefore, a human three-dimensional (3D) culture system was developed to examine the role of the fallopian fimbriae in serous tumorigenesis.

METHODS: Alginate matrix was utilized to support human fallopian fimbriae ex vivo. Fimbriae were cultured with factors hypothesized to contribute to carcinogenesis, namely; H2O2 (1mM) a mimetic of oxidative stress, insulin (5μg/ml) to stimulate glycolysis, and estradiol (E2, 10nM) which peaks before ovulation. Cultures were evaluated for changes in proliferation and p53 expression, criteria utilized to identify potential precursor lesions. Further, secretory factors were assessed after treatment with E2 to identify if steroid signaling induces a pro-tumorigenic microenvironment.

RESULTS: 3D fimbriae cultures maintained normal tissue architecture up to 7days, retaining both epithelial subtypes. Treatment of cultures with H2O2 or insulin significantly induced proliferation. However, p53 stabilization was unaffected by any particular treatment, although it was induced by ex vivo culturing. Moreover, E2-alone treatment significantly induced its canonical target PR and expression of IL8, a factor linked to poor outcome.

CONCLUSIONS: 3D alginate cultures of human fallopian fimbriae provide an important microphysiological model, which can be further utilized to investigate serous tumorigenesis originating from the fallopian tube.

Intravitreal AAV2.COMP-Ang1 prevents neurovascular degeneration in a murine model of diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the United States. The vision-threatening processes of neuroglial and vascular dysfunction in DR occur in concert, driven by hyperglycemia and propelled by a pathway of inflammation, ischemia, vasodegeneration, and breakdown of the blood retinal barrier. Currently, no therapies exist for normalizing the vasculature in DR. Here we show that a single intravitreal dose of adeno-associated virus serotype 2 encoding a more stable, soluble, and potent form of angiopoietin 1 (AAV2.COMP-Ang1) can ameliorate the structural and functional hallmarks of DR in Ins2Akita mice, with sustained effects observed through six months. In early DR, AAV2.COMP-Ang1 restored leukocyte-endothelial interaction, retinal oxygenation, vascular density, vascular marker expression, vessel permeability, retinal thickness, inner retinal cellularity, and retinal neurophysiological response to levels comparable to non-diabetic controls. In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally-delivered endothelial colony-forming cells by promoting their integration into the vasculature and thereby stemming further visual decline. AAV2.COMP-Ang1 single-dose gene therapy can prevent neurovascular pathology, support vascular regeneration, and stabilize vision in DR.

Attending Physician Variability: A Model of Four Supervisory Styles

Purpose: There is wide variability in how attending physician roles on teaching teams, including patient care and trainee learning, are enacted. This study sought to better understand variability by considering how different attendings configured and rationalized direct patient care, trainee oversight, and teaching activities. 

Method: Constructivist grounded theory guided iterative data collection and analyses. Data were interviews with 24 attending physicians from two academic centers in Ontario, Canada, in 2012. During interviews, participants heard a hypothetical presentation and reflected on it as though it were presented to their team during a typical admission case review. 

Results: Four supervisory styles were identified: direct care, empowerment, mixed practice, and minimalist. Driven by concerns for patient safety, direct care involves delegating minimal patient care responsibility to trainees. Focused on supporting trainees’ progressive independence, empowerment uses teaching and oversight strategies to ensure quality of care. In mixed practice, patient care is privileged over teaching and is adjusted on the basis of trainee competence and contextual features such as patient volume. Minimalist style involves a high degree of trust in senior residents, delegating most patient care, and teaching to them. Attendings rarely discussed their styles with the team. 

Conclusions: The model adds to the literature on variability in supervisory practice, showing that the four styles reflect different ways of responding to tensions in the role and context. This model could be refined through observational research exploring the impact of context on style development and enactment. Making supervisory styles explicit could support improvement of team competence.

Self-consistent modelling of line-driven hot-star winds with Monte Carlo radiation hydrodynamics

Radiative pressure exerted by line interactions is a prominent driver of outflows in astrophysical systems, being at work in the outflows emerging from hot stars or from the accretion discs of cataclysmic variables, massive young stars and active galactic nuclei. In this work, a new radiation hydrodynamical approach to model line-driven hot-star winds is presented. By coupling a Monte Carlo radiative transfer scheme with a finite volume fluid dynamical method, line-driven mass outflows may be modelled self-consistently, benefiting from the advantages of Monte Carlo techniques in treating multiline effects, such as multiple scatterings, and in dealing with arbitrary multidimensional configurations. In this work, we introduce our approach in detail by highlighting the key numerical techniques and verifying their operation in a number of simplified applications, specifically in a series of self-consistent, one-dimensional, Sobolev-type, hot-star wind calculations. The utility and accuracy of our approach are demonstrated by comparing the obtained results with the predictions of various formulations of the so-called CAK theory and by confronting the calculations with modern sophisticated techniques of predicting the wind structure. Using these calculations, we also point out some useful diagnostic capabilities our approach provides. Finally, we discuss some of the current limitations of our method, some possible extensions and potential future applications.

Compositional data-driven alternatives to single geochemical component maps

Conventional practice in Regional Geochemistry includes as a final step of any geochemical campaign the generation of a series of maps, to show the spatial distribution of each of the components considered. Such maps, though necessary, do not comply with the compositional, relative nature of the data, which unfortunately make any conclusion based on them sensitive
to spurious correlation problems. This is one of the reasons why these maps are never interpreted isolated. This contribution aims at gathering a series of statistical methods to produce individual maps of multiplicative combinations of components (logcontrasts), much in the flavor of equilibrium constants, which are designed on purpose to capture certain aspects of the data.
We distinguish between supervised and unsupervised methods, where the first require an external, non-compositional variable (besides the compositional geochemical information) available in an analogous training set. This external variable can be a quantity (soil density, collocated magnetics, collocated ratio of Th/U spectral gamma counts, proportion of clay particle fraction, etc) or a category (rock type, land use type, etc). In the supervised methods, a regression-like model between the external variable and the geochemical composition is derived in the training set, and then this model is mapped on the whole region. This case is illustrated with the Tellus dataset, covering Northern Ireland at a density of 1 soil sample per 2 square km, where we map the presence of blanket peat and the underlying geology. The unsupervised methods considered include principal components and principal balances
(Pawlowsky-Glahn et al., CoDaWork2013), i.e. logcontrasts of the data that are devised to capture very large variability or else be quasi-constant. Using the Tellus dataset again, it is found that geological features are highlighted by the quasi-constant ratios Hf/Nb and their ratio against SiO2; Rb/K2O and Zr/Na2O and the balance between these two groups of two variables; the balance of Al2O3 and TiO2 vs. MgO; or the balance of Cr, Ni and Co vs. V and Fe2O3. The largest variability appears to be related to the presence/absence of peat.

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3, the active form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked 1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.

Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.