Extended endocrine therapy in breast cancer: A basket of length-constraint feature selection metaheuristics to balance Type I against Type II errors.

Extended endocrine therapy beyond 5 years is of major concern to ER + breast cancer survivors. However, it might be unsuitable to apply routinely used genomic tests designed for early recurrence risks to distant recurrence within 10 years in extended treatment context. These tests initially aim at high sensitivities with Type I errors much higher than Type II. Having lower positive predictive values (PPVs), these tests can bring many false positives who might not need further treatment options to avoid adversely affecting quality of life. Alternatively, we proposed a top-down approach to the raised issues. We built 149 targeted genes from four genomic tests upon 381 ER-positive node-negative patients with either metastasis free beyond 10 years (n = 202) or metastasis within 10 years (n = 179). By a basket of SVM-wrapped length-constraint feature selection (LCFS), we discovered four genomic SVMs that traded off Type I against Type II errors. Two independent cohorts were used to validate disease outcome predictions. A 36-gene SVM balanced sensitivities with PPVs at good levels: 74% vs 76% on 10-fold cross validation (n = 347) and 75% vs 71% on a test set (n = 34). Neither Oncotype DX RS (cutoff = 18, 31, 60.97) nor PAM50 ROR-S (cutoff = 29, 53, 61.18) could. Independent cohorts showed the 36-gene SVM predicted disease free survival (n = 136, HR = 2.59; 95% CI, 1.4-4.8) and disease specific survival (n = 127, HR = 4.06; 95% CI, 1.63-10.11) better than RS (DFS, HR = 2.15; DSS, HR = 3.86) and ROR-S (DFS, HR = 2.29; DSS, HR = 2.76). The case study demonstrated how we identified a genomic test to balance Type I against Type II errors for risk stratification. The top-down approach centered around the LCFS-metaheuristics basket is a generic methodology for clinical decision-making and quality of life using targeted profiling data where the number of dimensions (p) is smaller than the number of samples (n).

Equilibration and "Thermalization" in the Adapted Caldeira-Leggett Model.

I explore the processes of equilibration exhibited by the Adapted Caldeira-Leggett (ACL) model, a small unitary "toy model" developed for numerical studies of quantum decoherence between an SHO and an environment. I demonstrate how dephasing allows equilibration to occur in a wide variety of situations. While the finite model size and other "unphysical" aspects prevent the notions of temperature and thermalization from being generally applicable, certain primitive aspects of thermalization can be realized for particular parameter values. I link the observed behaviors to intrinsic properties of the global energy eigenstates, and argue that the phenomena I observe contain elements which might be key ingredients that lead to ergodic behavior in larger more realistic systems. The motivations for this work range from curiosity about phenomena observed in earlier calculations with the ACL model to much larger questions related to the nature of equilibrium, thermalization, and the emergence of physical laws.

Barren Plateaus Preclude Learning Scramblers.

Scrambling processes, which rapidly spread entanglement through many-body quantum systems, are difficult to investigate using standard techniques, but are relevant to quantum chaos and thermalization. In this Letter, we ask if quantum machine learning (QML) could be used to investigate such processes. We prove a no-go theorem for learning an unknown scrambling process with QML, showing that it is highly probable for any variational Ansatz to have a barren plateau landscape, i.e., cost gradients that vanish exponentially in the system size. This implies that the required resources scale exponentially even when strategies to avoid such scaling (e.g., from Ansatz-based barren plateaus or no-free-lunch theorems) are employed. Furthermore, we numerically and analytically extend our results to approximate scramblers. Hence, our work places generic limits on the learnability of unitaries when lacking prior information.

Advanced Liquid Chromatography of Polyolefins Using Simultaneous Solvent and Temperature Gradients.

Olefin copolymers are complex polymer materials that exhibit multiple distributions in molecular properties such as molar mass, chemical composition, and branching. To address the multivariate molecular compositions, chromatographic protocols have been developed that synergistically combine solvent and temperature gradients. As representative examples, blends of olefin copolymers have been fractionated on porous graphitic carbon stationary phases. This is the first study that makes complementary use of solvent and temperature gradient interaction chromatography (SGIC and TGIC, respectively) to capitalize on the advantages of both techniques. In a first experimental setup, solvent and temperature gradients were used simultaneously and complex blends of low molar mass polyethylene and ethylene-co-1-octene copolymers were separated with high efficiency. The separation of oligomers was observed to be significantly better in SGIC as compared to TGIC, while comonomer blends could be separated in either TGIC or SGIC mode. In another innovation, a two-column setup was employed where the columns were placed in different temperature zones. It was demonstrated that the separation of both low and high comonomer content blends was improved significantly when the temperatures of the two zones were manipulated reasonably.

On the sintering of solution-based silver nanoparticle thin-films for sprayed and flexible antennas.

In this work, we report on the fabrication and characterization of sub-300 nm electrode films based on solution-processed silver nanoparticles (AgNPs). Following the deposition of the electrode material using a scalable and homogenous spray process, the films are treated with thermal or photonic sintering to promote the coalescence of the nanoparticles and in turn decrease the resistivity of the films. After sintering, a resistivity of 63 ± 13 nΩ m is achieved for the AgNP films, which is only by a factor of four larger than the literature value for bulk silver. Both post-deposition treatments show a similar performance with regard to the achieved resistivity. However, photonic sintering avoids the need for thermal annealing at substrate temperatures of 150 °C and above. In addition, the photonic sintering process can easily be embedded in a roll-to-roll process and is extremely fast with light exposure times below 3 ms. Thus, this manufacturing technique paves the way for the use of flexible substrates in electronics. As a simple and practical application, we present the use of AgNP films for antennas operating in the 5 GHz band on flexible polyethylene terephthalate substrate. An original coplanar design is employed for the fabrication of antennas with a single conductive layer that exhibit a maximum return loss and radiation of -27 dB and 95%, respectively.

Chemical Composition Fractionation of Olefin Plastomers/Elastomers by Solvent and Thermal Gradient Interaction Chromatography.

Olefin plastomers/elastomers are typically copolymers with high comonomer contents and low crystallinities. Therefore, the fractionation of these materials with crystallization-based methods is not feasible. On the other hand, solvent and temperature gradient interaction chromatography (SGIC and TGIC, respectively) are suitable techniques for the separation of olefin copolymers with regard to their chemical composition. In this study, the application ranges of both techniques are investigated and compared for ethylene-propylene (EP) copolymers. A linear dependency of ethylene content versus elution volume is obtained with SGIC in practically the whole ethylene range. In the case of TGIC, a linear dependency is obtained within certain ethylene content limits. The accessible ethylene content separation range for TGIC is 50-100 mol% ethylene, and a broader 26-100 mol% ethylene range is accessible for SGIC, the latter being the technique of choice in the analysis of EP rubbers.

Wireless Chipless System for Humidity Sensing.

This work describes a fully wireless sensory system where a chipless strategy is followed in the sensor part. Alternatively, to characterize only the sensing element, we present the response of the reader antenna when the sensing element is placed in its vicinity: changes in the parameter of interest are seen by the reader through inductive coupling, varying its frequency response. The sensing part consists of a LC circuit manufactured by printing techniques on a flexible substrate, whose electrical permittivity shows dependence with the moisture content. The measurement distance show significant differences in the frequency response: a change of 700 kHz is observed when the measurement is performed directly on the wireless chipless sensor between 20% and 80%RH, while this variation in frequency is reduced more than three times when measuring at the reader antenna with 5 mm distance between elements. Furthermore, we demonstrate the importance of the separation between reader and sensor to get a reliable measuring system.

iRDA: a new filter towards predictive, stable, and enriched candidate genes.

BACKGROUND: Gene expression profiling using high-throughput screening (HTS) technologies allows clinical researchers to find prognosis gene signatures that could better discriminate between different phenotypes and serve as potential biological markers in disease diagnoses. In recent years, many feature selection methods have been devised for finding such discriminative genes, and more recently information theoretic filters have also been introduced for capturing feature-to-class relevance and feature-to-feature correlations in microarray-based classification. METHODS: In this paper, we present and fully formulate a new multivariate filter, iRDA, for the discovery of HTS gene-expression candidate genes. The filter constitutes a four-step framework and includes feature relevance, feature redundancy, and feature interdependence in the context of feature-pairs. The method is based upon approximate Markov blankets, information theory, several heuristic search strategies with forward, backward and insertion phases, and the method is aiming at higher order gene interactions. RESULTS: To show the strengths of iRDA, three performance measures, two evaluation schemes, two stability index sets, and the gene set enrichment analysis (GSEA) are all employed in our experimental studies. Its effectiveness has been validated by using seven well-known cancer gene-expression benchmarks and four other disease experiments, including a comparison to three popular information theoretic filters. In terms of classification performance, candidate genes selected by iRDA perform better than the sets discovered by the other three filters. Two stability measures indicate that iRDA is the most robust with the least variance. GSEA shows that iRDA produces more statistically enriched gene sets on five out of the six benchmark datasets. CONCLUSIONS: Through the classification performance, the stability performance, and the enrichment analysis, iRDA is a promising filter to find predictive, stable, and enriched gene-expression candidate genes.

Accessibility of microRNA binding sites in metastable RNA secondary structures in the presence of SNPs.

MOTIVATION: We study microRNA (miRNA) bindings to metastable RNA secondary structures close to minimum free energy conformations in the context of single nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) concentration levels, i.e. whether features of miRNA bindings to metastable conformations could provide additional information supporting the differences in expression levels of the two sequences defined by a SNP. In our study, the instances [mRNA/3'UTR; SNP; miRNA] were selected based on strong expression level analyses, SNP locations within binding regions and the computationally feasible identification of metastable conformations. RESULTS: We identified 14 basic cases [mRNA; SNP; miRNA] of 3' UTR-lengths ranging from 124 up to 1078 nt reported in recent literature, and we analyzed the number, structure and miRNA binding to metastable conformations within an energy offset above mfe conformations. For each of the 14 instances, the miRNA binding characteristics are determined by the corresponding STarMir output. Among the different parameters we introduced and analyzed, we found that three of them, related to the average depth and average opening energy of metastable conformations, may provide supporting information for a stronger separation between miRNA bindings to the two alleles defined by a given SNP. AVAILABILITY AND IMPLEMENTATION: At http://kks.inf.kcl.ac.uk/MSbind.html the MSbind tool is available for calculating features of metastable conformations determined by putative miRNA binding sites.

Spinodal instabilities and super-Planckian excursions in natural inflation.

Models such as Natural Inflation that use pseudo-Nambu-Goldstone bosons as the inflaton are attractive for many reasons. However, they typically require trans-Planckian field excursions ΔΦ>MPl, due to the need for an axion decay constant f>MPl to have both a sufficient number of e-folds and values of ns,r consistent with data. Such excursions would in general require the addition of all other higher dimension operators consistent with symmetries, thus disrupting the required flatness of the potential and rendering the theory nonpredictive. We show that in the case of Natural Inflation, the existence of spinodal instabilities (modes with tachyonic masses) can modify the inflaton equations of motion to the point that versions of the model with f

Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis.

OBJECTIVES: To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA). METHODS: 33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured. RESULTS: Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes. DISCUSSION: These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.

Development of a novel assay for proprotein converting enzyme activity on a multiplex bead-based array system.

We describe the development of a novel, robust assay system for determining the changes in activity of proprotein converting enzymes. An assay for prolyl oligopeptidase (POP) activity was constructed using a peptide-streptavidin substrate coupled to magnetic microspheres and cleavage was detected by loss of streptavidin on the MAGPIX reader. Test analysis of postmortem pituitary extracts from schizophrenia patients showed an increase in POP activity compared to controls. The results were validated using both fluorometric and Western blot analyses for POP activity and immunoreactivity, respectively. The assays can be multiplexed for measuring the activity of multiple proprotein cleaving enzymes simultaneously in laboratory and clinical settings and should add valuable new information for conditions such as neuropsychiatric diseases, diabetes, endocrine dysfunction, and cancer, where effects on proteolysis of biologically active peptides play a key role.

The structural basis of MRI bone erosions: an assessment by microCT.

OBJECTIVE: To determine whether erosions appearing in MRI in patients with rheumatoid arthritis (RA) represent true erosions. METHODS: 50 RA patients received 1.5 T MRI and microCT (µCT) of the dominant hand. Erosion counts were assessed in coronal T1 weighted MRI sections and in coronal as well as axial µCT sections of the metacarpophalangeal (MCP) joints II-IV. Extent of erosions was assessed by RA MRI Score (RAMRIS) erosion score (MRI) and by three-dimensional assessment of erosion volume (µCT). RESULTS: 111 of the 600 evaluated joint regions showed erosions in the MRI and 137 in the µCT. In only 28 regions false negative lesions (µCT positive, MRI negative) were found, all of which were very small lesions with a volume of less than 10 mm(3). Only two results were false-positive (µCT negative, MRI positive). RAMRIS erosion scores were strongly correlated to erosion volumes in the µCT (Pearson's r=0.514, p<0.001). Mean RAMRIS erosion scores were below 1 with erosion volumes up to 1.5 mm(3), below 2 with erosion volumes up to 20 mm(3) and over 2 with volumes of more than 20 mm(3). DISCUSSION: MRI erosions are generally based on true cortical breaks as shown by µCT. MRI is sensitive to detect bone erosions and only very small lesions escape detection. Moreover, RAMRIS erosion scores are closely linked to the absolute size of bone erosions in the µCT.

Cosmic curvature from de Sitter equilibrium cosmology.

I show that the de Sitter equilibrium cosmology generically predicts observable levels of curvature in the Universe today. The predicted value of the curvature, Ω(k), depends only on the ratio of the density of nonrelativistic matter to cosmological constant density ρ(m)(0)/ρ(Λ) and the value of the curvature from the initial bubble that starts the inflation, Ω(k)(B). The result is independent of the scale of inflation, the shape of the potential during inflation, and many other details of the cosmology. Future cosmological measurements of ρ(m)(0)/ρ(Λ) and Ω(k) will open up a window on the very beginning of our Universe and offer an opportunity to support or falsify the de Sitter equilibrium cosmology.

Improved SEC-FTIR method for the characterization of multimodal high-density polyethylenes.

A size-exclusion chromatography-Fourier transform infrared spectroscopy (SEC-FTIR) method for the analysis of high-density polyethylene copolymers was developed, providing superior resolution for the determination of short-chain branching as a function of time and improved repeatability by hardware adaptation and processing optimization. SEC-FTIR for characterization of polyolefins is a compromising technique. Best resolution in terms of molecular weight and molecular weight distribution requires a very low sample solution concentration in size-exclusion chromatography while best results from online infrared (IR) spectroscopy require as high concentrations as possible. The signal-to-noise ratio at the IR detector could be increased significantly after application of a bandpass filter instead of a steel mesh attenuator and furthermore influences of system instabilities could be decreased by changes in data processing. Reliable short-chain branching information in the high molecular weight section in respect to accuracy and repeatability with better chromatographic resolution could be achieved.

Improving temperature gradient interaction chromatography of polyolefins by simultaneous use of different stationary phases.

Temperature gradient interaction chromatography (TGIC) at high temperatures is a powerful method for the chemical composition separation of polyolefins. TGIC is a two-step process where the sample is crystallized on the stationary phase at low temperature followed by the elution of the sample components using a temperature gradient towards high temperatures. For TGIC typically a porous graphitic carbon (PGC) stationary phase is used. The separation mechanism is based on crystallization and adsorption/desorption phenomena and it has been shown that co-crystallization and co-adsorption may affect the separation. The present study reports on the simultaneous use of a non-adsorptive and an adsorptive stationary phase (column) in series to utilize both crystallization and adsorption for improved separation in TGIC. A silica column is used as the non-adsorptive support to allow for the crystallization of the polyolefin sample in the absence of an adsorptive force followed by the typical PGC column for adsorption/desorption. Accordingly, the loci of crystallization and adsorption/desorption are well separated from each other and can be adjusted independently. This novel column setup allows the sample to be introduced slowly onto the second (adsorptive) column eliminating possible co-adsorption and poor selectivity. Low molar mass polyethylene comprising of oligomers with approximately C30C130 was used to illustrate the importance of a non-adsorptive column for improved separation. Utilizing a non-adsorptive silica column allows for higher dynamic flow rates during crystallization, which improves separation. Shorter adsorptive columns are found to be more efficient in this experimental protocol as compared to standard TGIC experiments. Smaller PGC column sizes result in reduced longitudinal and Eddy diffusion and, hence, higher resolution of low and high molar mass polyolefins.

Split-HaloTag imaging assay for sophisticated microscopy of protein-protein interactions in planta.

An ever-increasing number of intracellular multi-protein networks have been identified in plant cells. Split-GFP-based protein-protein interaction assays combine the advantages of in vivo interaction studies in a native environment with additional visualization of protein complex localization. Because of their simple protocols, they have become some of the most frequently used methods. However, standard fluorescent proteins present several drawbacks for sophisticated microscopy. With the HaloTag system, these drawbacks can be overcome, as this reporter forms covalent irreversible bonds with synthetic photostable fluorescent ligands. Dyes can be used in adjustable concentrations and are suitable for advanced microscopy methods. Therefore, we have established the Split-HaloTag imaging assay in plants, which is based on the reconstitution of a functional HaloTag protein upon protein-protein interaction and the subsequent covalent binding of an added fluorescent ligand. Its suitability and robustness were demonstrated using a well-characterized interaction as an example of protein-protein interaction at cellular structures: the anchoring of the molybdenum cofactor biosynthesis complex to filamentous actin. In addition, a specific interaction was visualized in a more distinctive manner with subdiffractional polarization microscopy, Airyscan, and structured illumination microscopy to provide examples of sophisticated imaging. Split-GFP and Split-HaloTag can complement one another, as Split-HaloTag represents an alternative option and an addition to the large toolbox of in vivo methods. Therefore, this promising new Split-HaloTag imaging assay provides a unique and sensitive approach for more detailed characterization of protein-protein interactions using specific microscopy techniques, such as 3D imaging, single-molecule tracking, and super-resolution microscopy.

Improving chromatographic separation of polyolefins on porous graphitic carbon stationary phases: effects of adsorption promoting solvent and column length.

The chromatographic separation of complex polyolefins on porous graphitic carbon stationary phases is strongly influenced by the composition of the mobile phase. Of particular interest is the effect of the chemical structure of the adsorption promoting solvent as this component of the mobile phase determines the adsorption-desorption behavior of the polyolefin molecules. In a systematic study, alkyl alcohols and linear alkanes are used as adsorption promoting solvents and the effect of the molecules' carbon chain length on chromatographic resolution is investigated. As representative examples, solvent gradient interaction chromatography experiments on polypropylene stereoisomers and ethylene-co-1-octene copolymers are presented. In a further study, the effect of increasing chromatographic column length on the solvent gradient separation of ethylene-co-1-octene copolymers is investigated. In summary, it is shown that the polypropylene stereoisomers are retained in 1-octanol as well as in n-decane and n-dodecane, allowing for identification of the individual stereoisomers in complex blends. For ethylene-co-1-octene copolymers it is shown that separation improves with increasing carbon chain length of the adsorption promoting solvent. Maximum resolution is obtained when a column length of 300 mm is used with 1-dodecanol as the adsorption promoting solvent.

Corrigendum: Long Non-coding RNA Structure and Function: Is There a Link?

[This corrects the article DOI: 10.3389/fphys.2018.01201.].

Decoherence of black hole superpositions by Hawking radiation.

An environment interacting with a system acquires information about it, e.g. about its location. The resulting decoherence is thought to be responsible for the emergence of the classical realm of our Universe out of the quantum substrate. However, this view of the emergence of the classical is sometimes dismissed as a consequence of insufficient isolation and, hence, as non-fundamental. In contrast to many other systems, a black hole can never be isolated from its Hawking radiation which carries information about its location, making this lack of isolation fundamental. Here we consider the decoherence of a "black hole Schrödinger cat"-a non-local superposition of a Schwarzschild black hole in two distinct locations-due to its Hawking radiation. The resulting decoherence rate turns out to be given by a surprisingly simple equation. Moreover, and in contrast to known cases of decoherence, this rate does not involve Planck's constant h.