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.

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 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.

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.

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.].

Cost-effective PEDOT:PSS Temperature Sensors Inkjetted on a Bendable Substrate by a Consumer Printer.

In this work, we report on a fabrication protocol to produce fully inkjet-printed temperature sensors on a bendable polyethylene terephthalate (PET) substrate. The sensing layer is made of polymer-based Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) ink that is electrically contacted by an underlying interdigitated electrode (IDE) structure based on a silver nanoparticle (AgNP) ink. Both inks are available commercially, and no further ink processing is needed to print them using a cost-effective consumer printer with standard cartridges. The fabricated sensor modules are tested for different IDE dimensions and post-deposition treatments of the AgNP film for their response to a temperature range of 20 to 70 °C and moisture range of 20 to 90% RH (relative humidity). Attributed to the higher initial resistance, sensor modules with a larger electrode spacing of 200 µm show a higher thermal sensitivity that is increased by a factor of 1.8 to 2.2 when compared to sensor modules with a 150 µm-spacing. In all cases, the sensors exhibit high linearity towards temperature and a response comparable to state of the art.

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.

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.

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

RNA has emerged as the prime target for diagnostics, therapeutics and the development of personalized medicine. In particular, the non-coding RNAs (ncRNAs) that do not encode proteins, display remarkable biochemical versatility. They can fold into complex structures and interact with proteins, DNA and other RNAs, modulating the activity, DNA targets or partners of multiprotein complexes. Thus, ncRNAs confer regulatory plasticity and represent a new layer of epigenetic control that is dysregulated in disease. Intriguingly, for long non-coding RNAs (lncRNAs, >200 nucleotides length) structural conservation rather than nucleotide sequence conservation seems to be crucial for maintaining their function. LncRNAs tend to acquire complex secondary and tertiary structures and their functions only impose very subtle sequence constraints. In the present review we will discuss the biochemical assays that can be employed to determine the lncRNA structural configurations. The implications and challenges of linking function and lncRNA structure to design novel RNA therapeutic approaches will also be analyzed.

A Handwriting Method for Low-Cost Gas Sensors.

In this study, we report on an automated method based on a handwritten technique for the fabrication of low-cost gas sensors based on carbon nanotube (CNT) networks. Taking advantage of the inherent low-cost, flexible, and uncomplicated characteristics of pen-based techniques and combining them with an automated robotic system allows for high-resolution patterns, high reproducibility, and relatively high throughput considering the limitations of parallel processing. To showcase this, gas sensors capable of sensing NH3, CO2, CO, and ethanol, as well as temperature and relative humidity, are fabricated and characterized displaying competitive performance in relation to previously reported devices. The presented process is compatible with a variety of solutions and inks and, as such, allows for an easy integration into existing printing and coating frameworks with the greatest advantage being the ease of creating prototypes because of the nonstringent material requirements.

In-Depth Study of Laser Diode Ablation of Kapton Polyimide for Flexible Conductive Substrates.

This work presents a detailed study of the photothermal ablation of Kapton® polyimide by a laser diode targeting its electrical conductivity enhancement. Laser-treated samples were structurally characterized using Scanning Electron Microscopy (SEM), Raman spectroscopy, X-ray Photoelectron Spectroscopy (XPS), as well as Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy. The results show that the laser-assisted ablation constitutes a simple one-step and environmental friendly method to induce graphene-derived structures on the surface of polyimide films. The laser-modified surface was also electrically characterized through the Transmission Line Method (TLM) aiming at the improvement of the conductivity of the samples by tuning the laser power and the extraction of the contact resistance of the electrodes. Once the laser-ablation process is optimized, the samples increase their conductivity up to six orders of magnitude, being comparable to that of graphene obtained by chemical vapor deposition or by the reduction of graphene-oxide. Additionally, we show that the contact resistance can be decreased down to promising values of ∼2 Ω when using silver-based electrodes.

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.

Biomimetic light-harvesting funnels for re-directioning of diffuse light.

Efficient sunlight harvesting and re-directioning onto small areas has great potential for more widespread use of precious high-performance photovoltaics but so far intrinsic solar concentrator loss mechanisms outweighed the benefits. Here we present an antenna concept allowing high light absorption without high reabsorption or escape-cone losses. An excess of randomly oriented pigments collects light from any direction and funnels the energy to individual acceptors all having identical orientations and emitting ~90% of photons into angles suitable for total internal reflection waveguiding to desired energy converters (funneling diffuse-light re-directioning, FunDiLight). This is achieved using distinct molecules that align efficiently within stretched polymers together with others staying randomly orientated. Emission quantum efficiencies can be >80% and single-foil reabsorption <0.5%. Efficient donor-pool energy funneling, dipole re-orientation, and ~1.5-2 nm nearest donor-acceptor transfer occurs within hundreds to ~20 ps. Single-molecule 3D-polarization experiments confirm nearly parallel emitters. Stacked pigment selection may allow coverage of the entire solar spectrum.

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.

Over-Stretching Tolerant Conductors on Rubber Films by Inkjet-Printing Silver Nanoparticles for Wearables.

The necessity to place sensors far away from the processing unit in smart clothes or artificial skins for robots may require conductive wirings on stretchable materials at very low-cost. In this work, we present an easy method to produce wires using only commercially available materials. A consumer grade inkjet printer was used to print a wire of silver nanoparticles with a sheet resistance below 1 Ω/sq. on a non-pre-strained sheet of elastic silicone. This wire was stretched more than 10,000 times and was still conductive afterwards. The viscoelastic behavior of the substrate results in a temporarily increased resistance that decreases to almost the original value. After over-stretching, the wire is conductive within less than a second. We analyze the swelling of the silicone due to the ink's solvent and the nanoparticle film on top by microscope and SEM images. Finally, a 60 mm long stretchable conductor was integrated onto wearables, and showed that it can bear strains of up to 300% and recover to a conductivity that allows the operation of an assembled LED assembled at only 1.8 V. These self-healing wires can serve as wiring and binary strain or pressure sensors in sportswear, compression underwear, and in robotic applications.

CRISPR/Cas9 editing reveals novel mechanisms of clustered microRNA regulation and function.

MicroRNAs (miRNAs) are important regulators of diverse physiological and pathophysiological processes. MiRNA families and clusters are two key features in miRNA biology. Here we explore the use of CRISPR/Cas9 as a powerful tool to delineate the function and regulation of miRNA families and clusters. We focused on four miRNA clusters composed of miRNA members of the same family, homo-clusters or different families, hetero-clusters. Our results highlight different regulatory mechanisms in miRNA cluster expression. In the case of the miR-497~195 cluster, editing of miR-195 led to a significant decrease in the expression of the other miRNA in the cluster, miR-497a. Although no gene editing was detected in the miR-497a genomic locus, computational simulation revealed alteration in the three dimensional structure of the pri-miR-497~195 that may affect its processing. In cluster miR-143~145 our results imply a feed-forward regulation, although structural changes cannot be ruled out. Furthermore, in the miR-17~92 and miR-106~25 clusters no interdependency in miRNA expression was observed. Our findings suggest that CRISPR/Cas9 is a powerful gene editing tool that can uncover novel mechanisms of clustered miRNA regulation and function.

Random versus Deterministic Descent in RNA Energy Landscape Analysis.

Identifying sets of metastable conformations is a major research topic in RNA energy landscape analysis, and recently several methods have been proposed for finding local minima in landscapes spawned by RNA secondary structures. An important and time-critical component of such methods is steepest, or gradient, descent in attraction basins of local minima. We analyse the speed-up achievable by randomised descent in attraction basins in the context of large sample sets where the size has an order of magnitude in the region of ~10(6). While the gain for each individual sample might be marginal, the overall run-time improvement can be significant. Moreover, for the two nongradient methods we analysed for partial energy landscapes induced by ten different RNA sequences, we obtained that the number of observed local minima is on average larger by 7.3% and 3.5%, respectively. The run-time improvement is approximately 16.6% and 6.8% on average over the ten partial energy landscapes. For the large sample size we selected for descent procedures, the coverage of local minima is very high up to energy values of the region where the samples were randomly selected from the partial energy landscapes; that is, the difference to the total set of local minima is mainly due to the upper area of the energy landscapes.