High on-chip gain spiral Al2O3:Er3+ waveguide amplifiers.

We demonstrate reactively sputtered Al2O3:Er3+ waveguide amplifiers with an erbium concentration of 3.9 × 1020 ions/cm3, capable of achieving over 30 dB small signal net gain at 1532 nm using bidirectional pumping at 1480 nm. We observe on chip output powers of 10.2-13.6 dBm of amplified signal power at 1532 nm for a 12.9 cm waveguide amplifier considering -25.4 dB of lumped coupling losses per facet. Annealing was used to improve the performance of the devices, which were patterned using electron beam lithography and reactive ion etching. This result, to our knowledge, represents record breaking on-chip internal net gain for Al2O3:Er3+ waveguide amplifiers, which show promise over other technologies due to wafer scalability and promise of easy monolithic integration with other material platforms to support a wide variety of applications.

Coulombic Surface-Ion Interactions Induce Nonlinear and Chemistry-Specific Charging Kinetics.

While important for many industrial applications, chemical reactions responsible for the charging of solids in water are often poorly understood. We theoretically investigate the charging kinetics of solid-liquid interfaces and find that the time-dependent equilibration of surface charge contains key information not only on the reaction mechanism, but also on the valency of the reacting ions. We construct a nonlinear differential equation describing surface charging by combining chemical Langmuir kinetics and electrostatic Poisson-Boltzmann theory. Our results reveal a clear distinction between late-time (near-equilibrium) and short-time (far-from-equilibrium) relaxation rates, the ratio of which contains information on the charge valency and ad- or desorption mechanism of the charging process. Similarly, we find that single-ion reactions can be distinguished from two-ion reactions, as the latter show an inflection point during equilibration. Interestingly, such inflection points are characteristic of autocatalytic reactions, and we conclude that the Coulombic ion-surface interaction is an autocatalytic feedback mechanism.

Crack barriers for thick SiN using dicing.

Silicon nitride (SiN) waveguides need to be thick to show low dispersion which is desired for nonlinear applications. However, high quality thick SiN produced by chemical vapour deposition (CVD) contains high internal stress, causing it to crack. Crack-free wafers with thick SiN can be produced by adding crack barriers. We demonstrate the use of dicing trenches as a simple single-step method to produce high quality (loss<0.5 dB/cm) crack-free SiN. We show Kerr-comb generation in a ring resonator to highlight the high quality and low dispersion of the waveguides.

Mode-splitting in a microring resonator for self-referenced biosensing.

Self-referenced biosensing based on mode-splitting on a microring resonator is experimentally demonstrated. A Bragg grating integrated on the surface of the ring provides coupling between the clockwise and counterclockwise travelling modes of the pristine ring resonator lifting their degeneracy. The amount of mode-splitting is directly related to the reflectivity of the grating and it is only affected by structurally modifying the grating. Environmental perturbations to the surroundings of the gratings, such as temperature and bulk refractive index variations, have a minor effect on the amount of mode-splitting. This principle allows the realization of a self-referenced sensing scheme based on the detection of variations of the mode-splitting induced by structural changes to the grating. In this work, a polymethyl methacrylate (PMMA) Bragg grating is integrated onto a ring resonator in Al2O3. It is shown both theoretically and experimentally that the amount of splitting of a resonance varies minimally under temperature or bulk refractive index perturbations. However, the structural change of attaching a layer of biomolecules inside the grating does affect its reflectivity and the amount of mode splitting present. This result represents the first proof-of-concept demonstration of an integrated mode-splitting biosensor insensitive to temperature and refractive index variations of the liquid matrix where the molecules to be detected are embedded. The reported results pave the road towards the realization of truly self-referenced biosensors.

Development of low-loss TiO2 waveguides.

TiO2 channel waveguides were fabricated using a DC sputter deposition process, followed by photolithography and reactive ion etching. A SiO2 cladding was deposited using evaporation. SEM, TEM and Raman measurements indicate the presence of both an amorphous and a crystalline phase. As the layer thickness increases, poly-crystalline structures start forming. Loss measurements were performed by imaging the scattered light from the top of the channel waveguides and fitting an exponential decay to the intensity profile. Propagation losses of 7.8 ± 0.52 dB/cm at a wavelength of 632.8 nm and 0.68 ± 0.46 dB/cm at a wavelength of 1010 nm were experimentally characterized.

Al2O3 microring resonators for the detection of a cancer biomarker in undiluted urine.

Concentrations down to 3 nM of the rhS100A4 protein, associated with human tumor development, have been detected in undiluted urine using an integrated sensor based on microring resonators in the emerging Al2O3 photonic platform. The fabricated microrings were designed for operation in the C-band (λ = 1565 nm) and exhibited a high-quality factor in air of 3.2 × 105. The bulk refractive index sensitivity of the devices was ~100 nm/RIU (for TM polarization) with a limit of detection of ~10-6 RIU. A surface functionalization protocol was developed to allow for the selective binding of the monoclonal antibodies designed to capture the target biomarker to the surface of the Al2O3 microrings. The detection of rhS100A4 proteins at clinically relevant concentrations in urine is a big milestone towards the use of biosensors for the screening and early diagnosis of different cancers. Biosensors based on this microring technology can lead to portable, multiplexed and easy-to-use point of care devices.

Venous thrombosis during olanzapine treatment: a complex association.

Olanzapine, a second generation antipsychotic, has previously been associated with an increased risk of venous thromboembolism (VTE). In this mini-review we describe a case of a thirty-year-old schizophrenic patient who was diagnosed with a deep venous thrombosis (DVT) six months after starting olanzapine therapy, as well as seventeen other VTE cases in patients using olanzapine reported to the Netherlands Pharmacovigilance Centre Lareb. In 14 of these reports, patients had reported additional risk factors for VTE. We found disproportionate Reporting Odds Ratios (RORs) in the global database VigiBase for olanzapine and the reactions deep vein thrombosis (ROR of 1.38 with a 95% CI (Confidence Interval) of 1.22-1.57) and pulmonary embolism (ROR of 1.99 with a 95% CI of 1.81-2.19). The mechanism behind the association of olanzapine with VTE could be explained by two risk factors, substantial weight gain and lethargy, both common side effects of olanzapine. So far, a direct effect of olanzapine on platelet aggregation or coagulation has not been found. Schizophrenic patients are more likely to have diagnostic delay in the diagnosis of VTE, as symptoms such as lethargy and impaired pain perception result in diminished pain perception and pain expression, while they are at increased risk of developing VTE. Currently no validated risk score is available for detection of psychiatric patients who might benefit from pharmacologic VTE prophylaxis. In patients developing a VTE while being treated with olanzapine, discontinuation of olanzapine could be considered based on the individual risk profile, control of psychotic symptoms and antipsychotic treatment options.

Revealing a Vacancy Analog of the Crowdion Interstitial in Simple Cubic Crystals.

Vacancies in simple cubic crystals of hard cubes are known to delocalize over one-dimensional chains of several lattice sites. Here, we use computer simulations to examine the structure and dynamics of vacancies in simple cubic crystals formed by hard cubes, right rhombic prisms (slanted cubes), truncated cubes, and particles interacting via a soft isotropic pair potential. We show that these vacancies form a vacancy analog of the crowdion interstitial, generating a strain field which follows a soliton solution of the sine-Gordon equation, and diffusing via a persistent random walk. Surprisingly, we find that the structure of these "voidions" is not significantly affected by changes in density, vacancy concentration, and even particle interaction. We explain this structure quantitatively using a one-dimensional model that includes the free-energy barrier particles have to overcome to slide between lattice sites and the effective pair interaction along this line. We argue that voidions are a robust phenomenon in systems of repulsive particles forming simple cubic crystals.

A simulation study on the phase behavior of hard rhombic platelets.

Using Monte Carlo simulations, we investigate the phase behavior of hard rhombic platelets as a function of the thickness of the platelets, T. The phase diagram displays a columnar phase and a crystal phase in which the platelets are stacked in columns that are arranged in a two-dimensional lattice. We find that the shape of the platelets determines the symmetry of the two-dimensional lattice, i.e., rhombic platelets form an oblique columnar phase and a simple monoclinic crystal phase. For sufficiently thick platelets, i.e., for a thickness-to-length ratio T/L>0.17, we find only an isotropic fluid, an oblique columnar phase, and a monoclinic crystal phase. Surprisingly, for an intermediate plate thickness, 0.083

High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy.

Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE-/- mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.

Removing grain boundaries from three-dimensional colloidal crystals using active dopants.

Using computer simulations we explore how grain boundaries can be removed from three-dimensional colloidal crystals by doping with a small fraction of active colloids. We show that for sufficient self-propulsion, the system is driven into a crystal-fluid coexistence. In this phase separated regime, the active dopants become mobile and spontaneously gather at the grain boundaries. The resulting surface melting and recrystallization of domains result in the motion of the grain boundaries over time and lead to the formation of a large single crystal. However, when the self-propulsion is too low to cause a phase separation, we observe no significant enhancement of grain growth.

Fabricating large two-dimensional single colloidal crystals by doping with active particles.

Using simulations we explore the behaviour of two-dimensional colloidal (poly)crystals doped with active particles. We show that these active dopants can provide an elegant new route to removing grain boundaries in polycrystals. Specifically, we show that active dopants both generate and are attracted to defects, such as vacancies and interstitials, which leads to clustering of dopants at grain boundaries. The active particles both broaden and enhance the mobility of the grain boundaries, causing rapid coarsening of the crystal domains. The remaining defects recrystallize upon turning off the activity of the dopants, resulting in a large-scale single-domain crystal.

Expression of a passenger miR-9* predicts favorable outcome in adults with acute myeloid leukemia less than 60 years of age.

In double-stranded miRNA/miRNA* duplexes, one of the strands represents an active miRNA, whereas another, known as a passenger strand (miRNA*), is typically degraded. MiR-9* is not detectable in normal myeloid cells. Here we show that miR-9* is expressed in 59% of acute myeloid leukemia (AML) cases and we investigate its clinical impact in 567 adults with de novo AML (age⩽60 years). AML cases with detectable miR-9* included a lower percentage of cases with favorable risk (P<0.001) as compared with those with no detectable miR-9*. High levels of miR-9* expression independently predicted for higher complete remission (odds ratio=1.28, P=0.013) and better event-free survival (EFS) (hazard ratio (HR)=0.86, P=0.001), relapse-free survival (RFS) (HR=0.84, P=0.008) and overall survival (OS) (HR=0.86, P=0.002). Among the subgroup of adverse risk patients, high miR-9* expressers had strikingly longer median survival than low miR-9* expressers (EFS: 16 vs 5 months, P=0.020; RFS: 12 vs 4, P=0.060; OS: 23 vs 8, P=0.021). Comparative transcriptome analysis suggests that miR-9* regulates genes involved in leukemogenesis, for example, MN1 and MLLT3. This is the first report showing that an miRNA* has prognostic value in AML.

Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG.

Aberrant post-transcriptional regulation by microRNAs (miRNAs) has been shown to be involved in the pathogenesis of acute myeloid leukemia (AML). In a previous study, we performed a large functional screen using a retroviral barcoded miRNA expression library. Here, we report that overexpression of miR-9/9* in myeloid 32D cell line (32D-miR-9/9*) had profound impact on granulocyte colony-stimulating factor-induced differentiation. Further in vitro studies showed that enforced expression of miR-9/9* blocked normal neutrophil development in 32D and in primary murine lineage-negative bone marrow cells. We examined the expression of miR-9/9* in a cohort of 647 primary human AMLs. In most cases, miR-9 and miR-9* were significantly upregulated and their expression levels varied according to AML subtype, with the highest expression in MLL-related leukemias harboring 11q23 abnormalities and the lowest expression in AML cases with t(8;21) and biallelic mutations in CEBPA. Gene expression profiling of AMLs with high expression of miR-9/9* and 32D-miR-9/9* identified ETS-related gene (Erg) as the only common potential target. Upregulation of ERG in 32D cells rescued miR-9/9*-induced block in neutrophil differentiation. Taken together, this study demonstrates that miR-9/9* are aberrantly expressed in most of AML cases and interfere with normal neutrophil differentiation by downregulation of ERG.

Behçet's disease, hospital-based prevalence and manifestations in the Rotterdam area.

INTRODUCTION: Behçet's disease is most prevalent in countries along the former Silk Road. Prevalence varies from 70-420 per 100,000 in Turkey, and 13.5-20 and 1-2 per 100,000 in Asia and Western Europe, respectively. Additionally, disease severity and morbidity might be correlated with ethnicity. We studied demography and morbidity in the Dutch cohort of patients with Behçet's disease and compared those with known figures. PATIENTS AND METHODS: The prevalence of Behçet's patients in the Rotterdam area was determined by comparing the total number of patients within the ethnic population with the number of patients diagnosed with Behçet's disease. Patient files of the Erasmus University Medical Centre (Erasmus MC) were reviewed for morbidity figures and compared with existing data. RESULTS: In total 84 Behçet's patients of Dutch, Turkish or Moroccan descent were identified in the Rotterdam area. Prevalence of Behçet's disease differed per ethnicity: 1, 71 and 39 per 100,000 for Dutch-Caucasians, Turks, and Moroccans, respectively. These figures are comparable with occurrence in West Turkey and Morocco. Within the studied Erasmus MC cohort no significant differences in morbidity appeared between the ethnic groups. However, uveitis and pustules were significantly more common in the Erasmus MC cohort as compared with UK, German, Turkish and Moroccan cohorts. DISCUSSION AND CONCLUSIONS: We present the first epidemiological study of Behçet's disease in the Netherlands. The prevalence of Behçet's disease in the studied Dutch region and in countries of ancestry is similar. Morbidity is equally spread, compared with other countries, but uveitis and pustules seem to be more common in the Netherlands.

Dynamical heterogeneities and defects in two-dimensional soft colloidal crystals.

In this paper we study a two-dimensional system of charged colloidal particles using Brownian dynamics simulations. We determine the phase diagram and investigate the dynamics of this system in the density regime where hexatic and solid phases are stable. We find that the dynamics in these phases is heterogeneous by means of the spontaneous formation and diffusion of highly mobile defects. We identify two key mechanisms associated with the areas of high mobility. The first mechanism involves the highly cooperative motion of a closed loop of particles which shift coherently along the loop until each particle has replaced the position of its predecessor in the chain. The second mechanism involves the spontaneous creation of vacancy-interstitial pairs which diffuse within the hexatic and solid phases. We further explore quantitatively the properties of the open-ended and closed rearrangement strings and find that in the crystal phase the string-size distribution can be approximately matched with a simple, random walk description of vacancies and interstitials on a lattice.

Determination of the positions and orientations of concentrated rod-like colloids from 3D microscopy data.

Confocal microscopy in combination with real-space particle tracking has proven to be a powerful tool in scientific fields such as soft matter physics, materials science and cell biology. However, 3D tracking of anisotropic particles in concentrated phases remains not as optimized compared to algorithms for spherical particles. To address this problem, we developed a new particle-fitting algorithm that can extract the positions and orientations of fluorescent rod-like particles from three dimensional confocal microscopy data stacks. The algorithm is tailored to work even when the fluorescent signals of the particles overlap considerably and a threshold method and subsequent clusters analysis alone do not suffice. We demonstrate that our algorithm correctly identifies all five coordinates of uniaxial particles in both a concentrated disordered phase and a liquid-crystalline smectic-B phase. Apart from confocal microscopy images, we also demonstrate that the algorithm can be used to identify nanorods in 3D electron tomography reconstructions. Lastly, we determined the accuracy of the algorithm using both simulated and experimental confocal microscopy data-stacks of diffusing silica rods in a dilute suspension. This novel particle-fitting algorithm allows for the study of structure and dynamics in both dilute and dense liquid-crystalline phases (such as nematic, smectic and crystalline phases) as well as the study of the glass transition of rod-like particles in three dimensions on the single particle level.

Density functional theory for chiral nematic liquid crystals.

Even though chiral nematic phases were the first liquid crystals experimentally observed more than a century ago, the origin of the thermodynamic stability of cholesteric states is still unclear. In this Rapid Communication we address the problem by means of a density functional theory for the equilibrium pitch of chiral particles. When applied to right-handed hard helices, our theory predicts an entropy-driven cholesteric phase, which can be either right or left handed, depending not only on the particle shape but also on the thermodynamic state. We explain the origin of the chiral ordering as an interplay between local nematic alignment and excluded-volume differences between left- and right-handed particle pairs.

Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice.

Vascular endothelial growth factor-B (VEGF-B) has been implicated to play a significant role in coronary vessel growth and endothelial uptake and transport of fatty acids in heart and skeletal muscle. Additionally, recent studies have shown that Vegf-b deficiency protects from high-fat diet (HFD)-induced diabetes and insulin resistance. We compared the cardiac function and the effects of HFD on body composition and glucose metabolism in two available Vegf-b knockout (Vegf-b(-/-) strains) mouse strains side by side with their respective littermate controls. We found no differences in HFD-induced weight gain, glucose tolerance or insulin resistance between the Vegf-b(-/-) strains and their littermate control mice. Furthermore, there was no difference in basal cardiac function and cardiac expression of genes involved in glucose or fatty acid metabolism between the Vegf-b(-/-) strains and their littermate control mice. We conclude that VEGF-B is dispensable for normal cardiac function under unstressed conditions and for HFD-induced metabolic changes.

Cervical cancer screening: on the way to a shift from cytology to full molecular screening.

Cytology-based nation-wide cervical screening has led to a substantial reduction of the incidence of cervical cancer in western countries. However, the sensitivity of cytology for the detection of high-grade precursor lesions or cervical cancer is limited; therefore, repeated testing is necessary to achieve program effectiveness. Additionally, adenocarcinomas and its precursors are often missed by cytology. Consequently, there is a need for a better screening test. The insight that infection with high-risk human papillomavirus (hrHPV) is the causal agent of cervical cancer and its precursors has led to the development of molecular tests for the detection of hrHPV. Strong evidence now supports the use of hrHPV testing in the prevention of cervical cancer. In this review, we will discuss the arguments in favor of, and concerns on aspects of implementation of hrHPV testing in primary cervical cancer screening, such as the age to start hrHPV-based screening, ways to increase screening attendance, requirements for candidate hrHPV tests to be used, and triage algorithms for screen-positive women.