Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.

Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.

Approaches to estimating inbreeding coefficients in clinical isolates of Plasmodium falciparum from genomic sequence data.

BACKGROUND: The advent of whole-genome sequencing has generated increased interest in modelling the structure of strain mixture within clinical infections of Plasmodium falciparum The life cycle of the parasite implies that the mixture of multiple strains within an infected individual is related to the out-crossing rate across populations, making methods for measuring this process in situ central to understanding the genetic epidemiology of the disease. RESULTS: This paper derives a set of new estimators for inferring inbreeding coefficients using whole genome sequence read count data from P. falciparum clinical samples, which provides resources to assess within-sample mixture that connect to extensive literatures in population genetics and conservation ecology. Features of the P. falciparum genome mean that standard methods for inbreeding coefficients and related F-statistics cannot be used directly. After reviewing an initial effort to estimate the inbreeding coefficient within clinical isolates of P. falciparum, several generalizations using both frequentist and Bayesian approaches are provided. A simpler, more intuitive frequentist estimator is shown to have nearly identical properties to the initial estimator both in simulation and in real data sets. The Bayesian approach connects these estimates to the Balding-Nichols model, a mainstay within genetic epidemiology, and a possible framework for more complex modelling. A simulation study shows strong performance for all estimators with as few as ten variants. Application to samples from the PF3K data set indicate significant across-country variation in within-sample mixture. Finally, a comparison with results from a recent mixture model for within-sample strain mixture show that inbreeding coefficients provide a strong proxy for these more complex models. CONCLUSIONS: This paper provides a set of methods for estimating inbreeding coefficients within P. falciparum samples from whole-genome sequence data, supported by simulation studies and empirical examples. It includes a substantially simple estimator with similar statistical properties to the estimator in current use. These methods will also be applicable to other species with similar life-cycles. Implementations of the methods described are available in an open-source R package pfmix. Estimates for the PF3K public data release are provide as part of this resource.

Inferring Strain Mixture within Clinical Plasmodium falciparum Isolates from Genomic Sequence Data.

We present a rigorous statistical model that infers the structure of P. falciparum mixtures-including the number of strains present, their proportion within the samples, and the amount of unexplained mixture-using whole genome sequence (WGS) data. Applied to simulation data, artificial laboratory mixtures, and field samples, the model provides reasonable inference with as few as 10 reads or 50 SNPs and works efficiently even with much larger data sets. Source code and example data for the model are provided in an open source fashion. We discuss the possible uses of this model as a window into within-host selection for clinical and epidemiological studies.

Mixture model of pottery decorations from Lake Chad Basin archaeological sites reveals ancient segregation patterns.

We present a new statistical approach to analysing an extremely common archaeological data type--potsherds--that infers the structure of cultural relationships across a set of excavation units (EUs). This method, applied to data from a set of complex, culturally heterogeneous sites around the Mandara mountains in the Lake Chad Basin, helps elucidate cultural succession through the Neolithic and Iron Age. We show how the approach can be integrated with radiocarbon dates to provide detailed portraits of cultural dynamics and deposition patterns within single EUs. In this context, the analysis supports ancient cultural segregation analogous to historical ethnolinguistic patterning in the region. We conclude with a discussion of the many possible model extensions using other archaeological data types.

A Bayesian approach to inferring the phylogenetic structure of communities from metagenomic data.

Metagenomics provides a powerful new tool set for investigating evolutionary interactions with the environment. However, an absence of model-based statistical methods means that researchers are often not able to make full use of this complex information. We present a Bayesian method for inferring the phylogenetic relationship among related organisms found within metagenomic samples. Our approach exploits variation in the frequency of taxa among samples to simultaneously infer each lineage haplotype, the phylogenetic tree connecting them, and their frequency within each sample. Applications of the algorithm to simulated data show that our method can recover a substantial fraction of the phylogenetic structure even in the presence of high rates of migration among sample sites. We provide examples of the method applied to data from green sulfur bacteria recovered from an Antarctic lake, plastids from mixed Plasmodium falciparum infections, and virulent Neisseria meningitidis samples.

InGaN/GaN multiple quantum wells grown on nonpolar facets of vertical GaN nanorod arrays.

Uniform GaN nanorod arrays are grown vertically by selective area growth on (left angle bracket 0001 right angle bracket) substrates. The GaN nanorods present six nonpolar {1⁻100} facets, which serve as growth surfaces for InGaN-based light-emitting diode quantum well active regions. Compared to growth on the polar {0001} plane, the piezoelectric fields in the multiple quantum wells (MQWs) can be eliminated when they are grown on nonpolar planes. The capability of growing ordered GaN nanorod arrays with different rod densities is demonstrated. Light emission from InGaN/GaN MQWs grown on the nonpolar facets is investigated by photoluminescence. Local emission from MQWs grown on different regions of GaN nanorods is studied by cathodoluminescence (CL). The core-shell structure of MQWs grown on GaN nanorods is investigated by cross-sectional transmission electron microscopy in both axial and radial directions. The results show that the active MQWs are predominantly grown on nonpolar planes of GaN nanorods, consistent with the observations from CL. The results suggest that GaN nanorod arrays are suitable growth templates for efficient light-emitting diodes.

Analysis and demonstration of coupling control in polymer microring resonators using photobleaching.

We describe postfabrication trimming of coupling in both laterally and vertically coupled polymer microring resonators (MRRs), using photobleaching. For both cases, a tapered directional-coupler-based simple analytical model is developed to simulate the change in coupling due to a bleaching-induced decrease in refractive index. A tightly focused laser beam spot (a few kilowatts per square centimeter) is used to precisely bleach the coupling region alone. Coupling control is achieved for (1) high-Q passive rings by bleaching the vertically coupled chromophore-doped bus waveguide, and for (2) laterally coupled electro-optic ring modulators, by bleaching both the ring and the waveguide in the coupling region. The power coupling ratio (PCR) of an undercoupled high-Q MRR filter is reduced by 0.54 percentage points for the TE mode, causing the MRR finesse to increase from a value of 72 to 108. For a ring modulator, the PCR was increased by 3.5 percentage points for the TM mode, causing a 6 dB increase in extinction ratio, to achieve a final value of nearly 25 dB. Phase/group-delay characterization confirmed that the ring was trimmed toward critical coupling.

Spectroscopy of a tapered-fiber photonic crystal waveguide coupler.

A spectroscopic technique based on a full four port modeling and measurement is developed and utilized to study a tapered- fiber photonic crystal waveguide coupler. The coupler is made by directly situating the tapered fiber on the defect region of a silicon membrane photonic crystal waveguide. The waveguide is lithographically terminated resulting a Fabry- Perot cavity. It turns out that the line-shape of the resonances is not merely a Lorentzian but can be constructed from that of the unloaded waveguide resonator. By knowing how the resonances broaden the experimental data is then fit and the coupling efficiency is extracted for the entire spectrum.

Learning to count: robust estimates for labeled distances between molecular sequences.

Researchers routinely estimate distances between molecular sequences using continuous-time Markov chain models. We present a new method, robust counting, that protects against the possibly severe bias arising from model misspecification. We achieve this robustness by generalizing the conventional distance estimation to incorporate the empirical distribution of site patterns found in the observed pairwise sequence alignment. Our flexible framework allows for computing distances based only on a subset of possible substitutions. From this, we show how to estimate labeled codon distances, such as expected numbers of synonymous or nonsynonymous substitutions. We present two simulation studies. The first compares the relative bias and variance of conventional and robust labeled nucleotide estimators. In the second simulation, we demonstrate that robust counting furnishes accurate synonymous and nonsynonymous distance estimates based only on easy-to-fit models of nucleotide substitution, bypassing the need for computationally expensive codon models. We conclude with three empirical examples. In the first two examples, we investigate the evolutionary dynamics of the influenza A hemagglutinin gene using labeled codon distances. In the final example, we demonstrate the advantages of using robust synonymous distances to alleviate the effect of convergent evolution on phylogenetic analysis of an HIV transmission network.

Dating the time of viral subtype divergence.

Precise dating of viral subtype divergence enables researchers to correlate divergence with geographic and demographic occurrences. When historical data are absent (that is, the overwhelming majority), viral sequence sampling on a time scale commensurate with the rate of substitution permits the inference of the times of subtype divergence. Currently, researchers use two strategies to approach this task, both requiring strong conditions on the molecular clock assumption of substitution rate. As the underlying structure of the substitution rate process at the time of subtype divergence is not understood and likely highly variable, we present a simple method that estimates rates of substitution, and from there, times of divergence, without use of an assumed molecular clock. We accomplish this by blending estimates of the substitution rate for triplets of dated sequences where each sequence draws from a distinct viral subtype, providing a zeroth-order approximation for the rate between subtypes. As an example, we calculate the time of divergence for three genes among influenza subtypes A-H3N2 and B using subtype C as an outgroup. We show a time of divergence approximately 100 years ago, substantially more recent than previous estimates which range from 250 to 3800 years ago.

Edge-emitting photonic crystal double-heterostructure nanocavity lasers with InAs quantum dot active material.

We report what is, to the best of our knowledge, the first demonstration of an edge-emitting photonic crystal nanocavity laser that is integrated with a photonic crystal waveguide. This demonstration is achieved with a double-heterostructure photonic crystal nanocavity incorporating an InAs quantum dot active region.

Tree and rate estimation by local evaluation of heterochronous nucleotide data.

MOTIVATION: Heterochronous gene sequence data is important for characterizing the evolutionary processes of fast-evolving organisms such as RNA viruses. A limited set of algorithms exists for estimating the rate of nucleotide substitution and inferring phylogenetic trees from such data. The authors here present a new method, Tree and Rate Estimation by Local Evaluation (TREBLE) that robustly calculates the rate of nucleotide substitution and phylogeny with several orders of magnitude improvement in computational time. METHODS: For the basis of its rate estimation TREBLE novelly utilizes a geometric interpretation of the molecular clock assumption to deduce a local estimate of the rate of nucleotide substitution for triplets of dated sequences. Averaging the triplet estimates via a variance weighting yields a global estimate of the rate. From this value, an iterative refinement procedure relying on statistical properties of the triplets then generates a final estimate of the global rate of nucleotide substitution. The estimated global rate is then utilized to find the tree from the pairwise distance matrix via an UPGMA-like algorithm. RESULTS: Simulation studies show that TREBLE estimates the rate of nucleotide substitution with point estimates comparable with the best of available methods. Confidence intervals are comparable with that of BEAST. TREBLE's phylogenetic reconstruction is significantly improved over the other distance matrix method but not as accurate as the Bayesian algorithm. Compared with three other algorithms, TREBLE reduces computational time by a minimum factor of 3000. Relative to the algorithm with the most accurate estimates for the rate of nucleotide substitution (i.e. BEAST), TREBLE is over 10,000 times more computationally efficient. AVAILABILITY: jdobrien.bol.ucla.edu/TREBLE.html

Lasing characteristics of InAs quantum dot microcavity lasers as a function of temperature and wavelength.

A Strong temperature dependence of microdisk lasers and photonic crystal nanocavity lasers with InAs quantum dot active regions is reported. These lasers operate at 1.3 microm at room temperature under optical pumping conditions. T(0, microdisk) = 31 K. T(0, photonic crystal nanocavity) = 14 K. The lasing threshold dependence on the lasing wavelength is also reported. We observe a minimum absorbed threshold pump power of 9 microW. This temperature and wavelength dependent lasing behavior is explained qualitatively by a simple model which attributes the experimental observations predominantly to surface recombination at threshold and the high quality factors of these cavities.

Reducing the out-of-plane radiation loss of photonic crystal waveguides on high-index substrates.

Two-dimensional photonic crystal linear defect waveguides on semiconductor substrates are studied. It is predicted that the out-of-plane radiation loss can be reduced by shifting one side of the photonic crystal cladding by one-half period with respect to the other along the propagation direction.

Calculated out-of-plane transmission loss for photonic-crystal slab waveguides.

A fully three-dimensional finite-difference time domain numerical model is presented for calculating the out-of-plane radiation loss in photonic-crystal slab waveguides. The propagation loss of a single-line defect waveguide in triangular-lattice photonic crystals is calculated for suspended-membrane, oxidized-lower-cladding, and deeply etched structures. The results show that low-loss waveguides are achievable for sufficiently suspended membranes and oxidized-lower-cladding structures.

Grating-assisted coupling of optical fibers and photonic crystal waveguides.

We propose and analyze a highly efficient method of coupling light from optical fibers to two-dimensional photonic crystal waveguides. Efficient coupling is achieved by positioning of a tapered fiber parallel to the linear defect, where the photonic crystal's cladding functions as a grating coupler and provides field confinement as well. Numerical simulations indicate that better than 90% transmission is possible with a full width at half-magnitude bandwidth of 12nm. It is shown that one can increase the bandwidth by increasing the field overlap between the two waveguides.

Lithographic fine-tuning of vertical cavity surface emitting laser-pumped two-dimensional photonic crystal lasers.

Lithographic tuning of operating wavelengths in a photonic crystal laser array is demonstrated. The photonic crystal lattice constant is varied by 2 nm between elements of the array, and a wavelength spacing of approximately 4 nm is achieved.