Genetic footprints of a rapid and large-scale range expansion: the case of cyclic common vole in Spain.

In the Anthropocene, many species are rapidly shifting their ranges in response to human-driven habitat modifications. Studying patterns and genetic signatures of range shifts helps to understand how species cope with environmental disturbances and predict future shifts in the face of global environmental change. We investigated the genetic signature of a contemporary wide-range expansion observed in the Iberian common vole Microtus arvalis asturianus shortly after a colonization event. We used mtDNA and microsatellite data to investigate patterns of genetic diversity, structure, demography, and gene flow across 57 localities covering the historical range of the species and the newly colonized area. The results showed a genetic footprint more compatible with a true range expansion (i.e. the colonization of previously unoccupied areas), than with a model of "colonization from within" (i.e. local expansions from small, unnoticed populations). Genetic diversity measures indicated that the source population was likely located at the NE of the historical range, with a declining gradient of genetic diversity towards the more recently invaded areas. At the expansion front, we observed the greatest gene flow and smallest pairwise differences between nearby localities. Both natural landscape features (rivers) and recent anthropogenic barriers (roads, railways) explained a large proportion of genetic variance among populations and had a significant impact on the colonization pathways used by voles.

In situx-ray analysis of misfit strain and curvature of bent polytypic GaAs-InxGa1-xAs core-shell nanowires.

Misfit strain in core-shell nanowires can be elastically released by nanowire bending in case of asymmetric shell growth around the nanowire core. In this work, we investigate the bending of GaAs nanowires during the asymmetric overgrowth by an InxGa1-xAs shell caused by avoiding substrate rotation. We observe that the nanowire bending direction depends on the nature of the substrate's oxide layer, demonstrated by Si substrates covered by native and thermal oxide layers. Further, we follow the bending evolution by time-resolvedin situx-ray diffraction measurements during the deposition of the asymmetric shell. The XRD measurements give insight into the temporal development of the strain as well as the bending evolution in the core-shell nanowire.

Beam damage of single semiconductor nanowires during X-ray nanobeam diffraction experiments.

Nanoprobe X-ray diffraction (nXRD) using focused synchrotron radiation is a powerful technique to study the structural properties of individual semiconductor nanowires. However, when performing the experiment under ambient conditions, the required high X-ray dose and prolonged exposure times can lead to radiation damage. To unveil the origin of radiation damage, a comparison is made of nXRD experiments carried out on individual semiconductor nanowires in their as-grown geometry both under ambient conditions and under He atmosphere at the microfocus station of the P08 beamline at the third-generation source PETRA III. Using an incident X-ray beam energy of 9 keV and photon flux of 1010 s-1, the axial lattice parameter and tilt of individual GaAs/In0.2Ga0.8As/GaAs core-shell nanowires were monitored by continuously recording reciprocal-space maps of the 111 Bragg reflection at a fixed spatial position over several hours. In addition, the emission properties of the (In,Ga)As quantum well, the atomic composition of the exposed nanowires and the nanowire morphology were studied by cathodoluminescence spectroscopy, energy-dispersive X-ray spectroscopy and scanning electron microscopy, respectively, both prior to and after nXRD exposure. Nanowires exposed under ambient conditions show severe optical and morphological damage, which was reduced for nanowires exposed under He atmosphere. The observed damage can be largely attributed to an oxidation process from X-ray-induced ozone reactions in air. Due to the lower heat-transfer coefficient compared with GaAs, this oxide shell limits the heat transfer through the nanowire side facets, which is considered as the main channel of heat dissipation for nanowires in the as-grown geometry.

Efficient adjustable light couplers of integrated III-V nanowire emitters on silicon waveguides based on ring resonators.

The development of integrated vertical III-V nanowire (NW) stimulated emitters in silicon photonics while achieving an efficient light coupling through vertical III-V NW lasers into horizontal optical silicon waveguides is demanding. This is mainly due to the directionality and contradiction of the simultaneously satisfied low threshold stimulated emission conditions of the vertical NWs and efficient light coupling from the NW emitters into the horizontal silicon waveguide. However, we propose a new, to the best of our knowledge, design by taking advantage of resonating features of ring structures and theoretically demonstrate that an interfacial ring resonator between GaAs NW emitters and the silicon waveguide achieves a coupling efficiency up to about 70% at a given wavelength. We also show that the interfacial resonator enables us to adjust the coupling efficiency from about 10% to over 70%. The adjustable coupling efficiency might also be a solution to compromise between the low threshold stimulated emission of NWs and efficient light coupling for realizing efficient silicon couplers based on integrated III-V NW lasers in silicon photonics. Besides the simple fabrication process compared to counterparts, we believe that the novel structure is promising for future optical on-chip data communication in silicon photonics, and the results are expandable to varying wavelengths and materials.

Correlated Nanoscale Analysis of the Emission from Wurtzite versus Zincblende (In,Ga)As/GaAs Nanowire Core-Shell Quantum Wells.

While the properties of wurtzite GaAs have been extensively studied during the past decade, little is known about the influence of the crystal polytype on ternary (In,Ga)As quantum well structures. We address this question with a unique combination of correlated, spatially resolved measurement techniques on core-shell nanowires that contain extended segments of both the zincblende and wurtzite polytypes. Cathodoluminescence hyperspectral imaging reveals a blue-shift of the quantum well emission energy by 75 ± 15 meV in the wurtzite polytype segment. Nanoprobe X-ray diffraction and atom probe tomography enable k·p calculations for the specific sample geometry to reveal two comparable contributions to this shift. First, there is a 30% drop in In mole fraction going from the zincblende to the wurtzite segment. Second, the quantum well is under compressive strain, which has a much stronger impact on the hole ground state in the wurtzite than in the zincblende segment. Our results highlight the role of the crystal structure in tuning the emission of (In,Ga)As quantum wells and pave the way to exploit the possibilities of three-dimensional band gap engineering in core-shell nanowire heterostructures. At the same time, we have demonstrated an advanced characterization toolkit for the investigation of semiconductor nanostructures.

Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer.

BACKGROUND: We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor 'dimensions' were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer. METHODS: Tumor dimensions, PC1-PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan-Meier curves. RESULTS: Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 [Formula: see text] 10-7 and p = 0.036), remaining significant after correction for standard clinical-pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 [Formula: see text] 10-12). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage. CONCLUSIONS: Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical-pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.

Work function of GaAs(hkl) and its modification using PEI: mechanisms and substrate dependence.

Spin-coating of poly(ethylenimine) (PEI) has been used to reduce the work function of GaAs (001), (110), (111)A and (111)B. The magnitude of the reduction immediately after coating varies significantly from 0.51 eV to 0.69 eV and depends on the surface crystal face, on the GaAs bulk doping and on the atomic termination of the GaAs. For all samples, the work function reduction shrinks in ambient air over the first 20 hours after spin coating, but reductions around 0.2-0.3 eV persist after 1 year of storage in air. Core-level photoemission of thin film PEI degradation in air is consistent with a two-stage reaction with CO2 and H2O previously proposed in carbon capture studies. The total surface dipole from PEI coating is consistent with a combination of internal neutral amine dipole and an interface dipole whose magnitude depends on the surface termination. The contact potential difference measured by Kelvin probe force microscopy on a cleaved GaAs heterostructure is smaller on p-doped regions. This can be explained by surface doping due to the PEI, which increases the band bending on p-doped GaAs where Fermi level pinning is weak. Both surface doping and surface dipole should be accounted for when considering the effect of PEI coated on a semiconductor surface.

Targeting the lipid metabolic axis ACSL/SCD in colorectal cancer progression by therapeutic miRNAs: miR-19b-1 role.

An abnormal acyl-CoA synthetase/stearoyl-CoA desaturase (ACSL/SCD) lipid network fuels colon cancer progression, endowing cells with invasive and migratory properties. Therapies against this metabolic network may be useful to improve clinical outcomes. Because micro-RNAs (miRNAs/miRs) are important epigenetic regulators, we investigated novel miRNAs targeting this pro-tumorigenic axis; hence to be used as therapeutic or prognostic miRNAs. Thirty-one putative common miRNAs were predicted to simultaneously target the three enzymes comprising the ACSL/SCD network. Target validation by quantitative RT-PCR, Western blotting, and luciferase assays showed miR-544a, miR-142, and miR-19b-1 as major regulators of the metabolic axis, ACSL/SCD Importantly, lower miR-19b-1 expression was associated with a decreased survival rate in colorectal cancer (CRC) patients, accordingly with ACSL/SCD involvement in patient relapse. Finally, miR-19b-1 regulated the pro-tumorigenic axis, ACSL/SCD, being able to inhibit invasion in colon cancer cells. Because its expression correlated with an increased survival rate in CRC patients, we propose miR-19b-1 as a potential noninvasive biomarker of disease-free survival and a promising therapeutic miRNA in CRC.

Self-Assembly of InAs Nanostructures on the Sidewalls of GaAs Nanowires Directed by a Bi Surfactant.

Surface energies play a dominant role in the self-assembly of three-dimensional (3D) nanostructures. In this Letter, we show that using surfactants to modify surface energies can provide a means to externally control nanostructure self-assembly, enabling the synthesis of novel hierarchical nanostructures. We explore Bi as a surfactant in the growth of InAs on the {11̅0} sidewall facets of GaAs nanowires. The presence of surface Bi induces the formation of InAs 3D islands by a process resembling the Stranski-Krastanov mechanism, which does not occur in the absence of Bi on these surfaces. The InAs 3D islands nucleate at the corners of the {11̅0} facets above a critical shell thickness and then elongate along ⟨110⟩ directions in the plane of the nanowire sidewalls. Exploiting this growth mechanism, we realize a series of novel hierarchical nanostructures, ranging from InAs quantum dots on single {11̅0} nanowire facets to zigzag-shaped nanorings completely encircling nanowire cores. Photoluminescence spectroscopy and cathodoluminescence spectral line scans reveal that small surfactant-induced InAs 3D islands behave as optically active quantum dots. This work illustrates how surfactants can provide an unprecedented level of external control over nanostructure self-assembly.

Quantum Dot Self-Assembly Driven by a Surfactant-Induced Morphological Instability.

In strained heteroepitaxy, two-dimensional layers can exhibit a critical thickness at which three-dimensional islands self-assemble, relieving misfit strain at the cost of an increased surface area. Here we show that such a morphological phase transition can be induced on demand using surfactants. We explore Bi as a surfactant in the growth of InAs on GaAs(110), and find that the presence of surface Bi induces Stranski-Krastanov growth of 3D islands, while growth without Bi always favors 2D layer formation. Exposing a static two monolayer thick InAs layer to Bi rapidly transforms the layer into 3D islands. Density functional theory calculations reveal that Bi as well as Sb reduce the energetic cost of 3D island formation by modifying surface energies. These 3D nanostructures behave as optically active quantum dots. This work illustrates how surfactants can enable quantum dot self-assembly where it otherwise would not occur.

A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Whole genome prediction of bladder cancer risk with the Bayesian LASSO.

To build a predictive model for urothelial carcinoma of the bladder (UCB) risk combining both genomic and nongenomic data, 1,127 cases and 1,090 controls from the Spanish Bladder Cancer/EPICURO study were genotyped using the HumanHap 1M SNP array. After quality control filters, genotypes from 475,290 variants were available. Nongenomic information comprised age, gender, region, and smoking status. Three Bayesian threshold models were implemented including: (1) only genomic information, (2) only nongenomic data, and (3) both sources of information. The three models were applied to the whole population, to only nonsmokers, to male smokers, and to extreme phenotypes to potentiate the UCB genetic component. The area under the ROC curve allowed evaluating the predictive ability of each model in a 10-fold cross-validation scenario. Smoking status showed the highest predictive ability of UCB risk (AUCtest = 0.62). On the other hand, the AUC of all genetic variants was poorer (0.53). When the extreme phenotype approach was applied, the predictive ability of the genomic model improved 15%. This study represents a first attempt to build a predictive model for UCB risk combining both genomic and nongenomic data and applying state-of-the-art statistical approaches. However, the lack of genetic relatedness among individuals, the complexity of UCB etiology, as well as a relatively small statistical power, may explain the low predictive ability for UCB risk. The study confirms the difficulty of predicting complex diseases using genetic data, and suggests the limited translational potential of findings from this type of data into public health interventions.

One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes.

The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622).

Role of re-growth interface preparation process for spectral line-width reduction of single InAs site-controlled quantum dots.

We present growth and optical characterization measurements of single InAs site-controlled quantum dots (SCQDs) grown by molecular beam epitaxy on GaAs (001) patterned substrates by atomic force microscopy oxidation lithography. InAs SCQDs directly grown on the patterned surface were used as a seed layer and strain template for the nucleation of optically active single InAs SCQDs. The preservation of the initial geometry of the engraved pattern motifs after the re-growth interface preparation process, the lack of buffer layer growth prior to InAs seed layer deposition and the development of suitable growth conditions provide us an improvement of the SCQDs' active layer optical properties while retaining a high ratio of single occupation (89%). In this work a fivefold reduction of the average optical line-width from 870 µeV to 156 µeV for InAs SCQDs located 15 nm from the re-growth interface is obtained by increasing the temperature of the initial thermal treatment step of the re-growth interface from 490 °C to 530 °C.

Bladder cancer and seroreactivity to BK, JC and Merkel cell polyomaviruses: the Spanish bladder cancer study.

An infectious etiology for bladder cancer has long been suspected. Merkel cell virus (MCV), BKV and JCV polyomaviruses are possible causative agents but data remain scarce. Therefore, we evaluated the seroresponse to these three polyomaviruses in association with bladder cancer risk. 1,135 incident bladder cancer subjects from five Spanish regions and 982 hospital controls matched by sex, age and region were included. 99% of cases were urothelial-cell carcinomas. Antibody response against MCV, BKV and JCV was measured by enzyme immunoassay using Virus-Like-Particles. Our results show a similar seroprevalence in cases and controls: 64/60% for BKV, 83/82% for MCV and 87/83% for JCV. However, among seropositive subjects, higher median seroreactivities were observed in cases compared to controls for BKV (0.84 vs. 0.70, p-value = 0.009) and MCV (1.81 vs. 0.65, p-value < 0.001). Increased bladder cancer risk was observed for BKV (OR = 1.4, 95%CI 1.04-1.8) and for MCV (OR = 1.5, 95%CI 1.2-1.9), when comparing highest to lowest seroreactivity tertiles. The associations of BKV and MCV with bladder cancer were independent of each other and neither smoking status nor disease stage and grade modified them. Furthermore, no association was observed between seroresponse to JCV and bladder cancer. Therefore, we conclude that BKV and MCV polyomavirus infection could be related to an increased bladder cancer risk.

High quality factor GaAs-based photonic crystal microcavities by epitaxial re-growth.

We investigate L7 photonic crystal microcavities (PCMs) fabricated by epitaxial re-growth of GaAs pre-patterned substrates, containing InAs quantum dots. The resulting PCMs show hexagonal shaped nano-holes due to the development of preferential crystallographic facets during the re-growth step. Through a careful control of the fabrication processes, we demonstrate that the photonic modes are preserved throughout the process. The quality factor (Q) of the photonic modes in the re-grown PCMs strongly depends on the relative orientation between photonic lattice and crystallographic directions. The optical modes of the re-grown PCMs preserve the linear polarization and, for the most favorable orientation, a 36% of the Q measured in PCMs fabricated by the conventional procedure is observed, exhibiting values up to ~6000. The results aim to the future integration of site-controlled QDs with high-Q PCMs for quantum photonics and quantum integrated circuits.

Pulmonary rehabilitation after total laryngectomy: a randomized cross-over clinical trial comparing two different heat and moisture exchangers (HMEs).

Post-laryngectomy heat and moisture exchanger (HME) use is known to have a beneficial effect on tracheal climate, pulmonary symptoms and related aspects. This study aims to investigate differences in clinical effects between the first and second generation Provox HMEs. The second generation (Provox XtraHME) has better humidification properties than the first generation (Provox HME), and has been shown to further improve tracheal climate. Forty-five laryngectomized patients, who were already using an HME, participated in a prospective, randomized cross-over clinical study in which each HME was used for 6 weeks. Results showed that for most parameters studied, the second generation HME performed equally well or better than the first generation HME. The improvement in tracheal climate translated into patients reporting significantly less tracheal dryness with the second generation than with the first generation (p = 0.039). Using an HME with better humidification properties is related to a reduction in tracheal dryness in our study population.

Chronic Achilles rupture reconstructed with Achilles tendon allograft: a case report.

Chronic ruptures of the Achilles tendon are more difficult to treat than acute tendon rupture. It has been shown that surgical treatment of chronic Achilles tendon rupture provides better functional results than nonoperative treatment. We present a case of neglected Achilles tendon rupture with a 12-cm defect that was repaired using an Achilles tendon allograft with interferential screws to fix the graft in the calcaneus. The patient recovered his ankle function to normal activities after rehabilitation.

[Basic principles for the development of biomarkers in oncology]. / Principios básicos para el desarrolo de biomarcadores en oncología.

The accelerated expansion of the knowledge of genetic and molecular basics of cancer, together with the recent development of molecular biology techniques, have had a significant impact in the field of oncology, among other medical disciplines. So, over the last few years, we are crossing from an empiricism-based model to an evidence-based model in which drugs are adapted depending of the molecular alterations which result crucial for tumor development (both for carcinogenesis and acquisition of an aggressive phenotype leading to tumor invasion and resistance to therapy). The molecular alterations /variations offer the possibility of being detected and used as biomarkers in clinical practice. Biomarkers may have multiple applications in the field of oncology, from determining the risk to suffer the disease to prediction of response to therapy, including diagnosis, prognosis and disease monitoring, with the final aim of performing a more personalized medicine and achieving greater efficacy for the therapies selected, diminishing each therapy's own adverse events. Considering the importance biomarkers may get to have in clinical decision making, it is basic that their development is performed under straight evaluation and validation rules. In this article we review the various types of biomarkers and the basic methodological principles for their development, validation and subsequent clinical application.

Exploiting flux shadowing for strain and bending engineering in core-shell nanowires.

Here we report on the non-uniform shell growth of InxGa1-xAs on the GaAs nanowire (NW) core by molecular beam epitaxy (MBE). The growth was realized on pre-patterned silicon substrates with the pitch size (p) ranging from 0.1 µm to 10 µm. Considering the preferable bending direction with respect to the MBE cells as well as the layout of the substrate pattern, we were able to modify the strain distribution along the NW growth axis and the subsequent bending profile. For NW arrays with a high number density, the obtained bending profile of the NWs is composed of straight (barely-strained) and bent (strained) segments with different lengths which depend on the pitch size. A precise control of the bent and straight NW segment length provides a method to design NW based devices with length selective strain distribution.