Variation in _PNPLA3_ is associated with outcomes in alcoholic liver disease

Two recent genome-wide association studies have described associations of SNP variants in _PNPLA3_ with nonalcoholic fatty liver and plasma liver enzyme levels in population based cohorts. We investigated the contributions of these variants to clinical outcomes in Mestizo subjects with a history of excessive alcohol consumption. We show that non-synonymous variant rs738409[G] (I148M) in _PNPLA3_ is strongly associated with alcoholic liver disease and progression to alcoholic cirrhosis (unadjusted OR = 2.25, P = 1.7x10^-10^; ancestry-adjusted OR = 1.79, P = 1.9x10^-5^)

Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease-Causing Point Mutations

Despite intense study of the neurofibromatosis type 2 (NF2) tumor-suppressor protein merlin, the biological properties and tumor-suppressor functions of merlin are still largely unknown. In this study, we examined the molecular activities of NF2-causing mutant merlin proteins in transfected mammalian cells, to elucidate the merlin properties that are critical for tumor-suppressor function. Most important, we found that 80% of the merlin mutants studied significantly altered cell adhesion, causing cells to detach from the substratum. This finding implies a function for merlin in regulating cell-matrix attachment, and changes in cell adhesion caused by mutant protein expression may be an initial step in the pathogenesis of NF2. In addition, five different mutations in merlin caused a significant increase in detergent solubility of merlin compared to wild type, indicating a decreased ability to interact with the cytoskeleton. Although not correlated to the cell-adhesion phenotype, four missense mutations decreased the binding of merlin to the ERM-interacting protein EBP-50, implicating this interaction in merlin inhibition of cell growth. Last, we found that some NF2 point mutations in merlin most closely resembled gain-of-function alleles in their cellular phenotype, which suggests that mutant NF2 alleles may not always act in a loss-of-function manner, as had been assumed, but may include a spectrum of allelic types with different phenotypic effects on the function of the protein. In aggregate, these cellular phenotypes provide a useful assay for identifying the functional domains and molecular partners necessary for merlin tumor-suppressor activity

Clinical validity assessment of a breast cancer risk model combining genetic and clinical information

_Background:_ The extent to which common genetic variation can assist in breast cancer (BCa) risk assessment is unclear. We assessed the addition of risk information from a panel of BCa-associated single nucleotide polymorphisms (SNPs) on risk stratification offered by the Gail Model.

_Methods:_ We selected 7 validated SNPs from the literature and genotyped them among white women in a nested case-control study within the Women’s Health Initiative Clinical Trial. To model SNP risk, previously published odds ratios were combined multiplicatively. To produce a combined clinical/genetic risk, Gail Model risk estimates were multiplied by combined SNP odds ratios. We assessed classification performance using reclassification tables and receiver operating characteristic (ROC) curves. 

_Results:_ The SNP risk score was well calibrated and nearly independent of Gail risk, and the combined predictor was more predictive than either Gail risk or SNP risk alone. In ROC curve analysis, the combined score had an area under the curve (AUC) of 0.594 compared to 0.557 for Gail risk alone. For reclassification with 5-year risk thresholds at 1.5% and 2%, the net reclassification index (NRI) was 0.085 (Z = 4.3, P = 1.0×10^-5^). Focusing on women with Gail 5-year risk of 1.5-2% results in an NRI of 0.195 (Z = 3.8, P = 8.6×10^−5^).

_Conclusions:_ Combining clinical risk factors and validated common genetic risk factors results in improvement in classification of BCa risks in white, postmenopausal women. This may have implications for informing primary prevention and/or screening strategies. Future research should assess the clinical utility of such strategies.
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Mid-infrared spectroscopy with a broadly tunable thin-film lithium niobate optical parametric oscillator

Mid-infrared spectroscopy, an important and widespread technique for sensing molecules, has encountered barriers stemming from sources either limited in tuning range or excessively bulky for practical field use. We present a compact, efficient, and broadly tunable optical parametric oscillator (OPO) device surmounting these challenges. Leveraging a dispersion-engineered singly-resonant OPO implemented in thin-film lithium niobate-on-sapphire, we achieve broad and controlled tuning over an octave, from 1.5 to 3.3 microns by combining laser and temperature tuning. The device generates > 25 mW of mid-infrared light at 3.2 microns, offering a power conversion efficiency of 15% (45% quantum efficiency). We demonstrate the tuning and performance of the device by successfully measuring the spectra of methane and ammonia, verifying our approach's relevance for gas sensing. Our device signifies an important advance in nonlinear photonics miniaturization and brings practical field applications of high-speed and broadband mid-infrared spectroscopy closer to reality.Comment: 19 pages, 11 figure

Integrated Quantum Optical Phase Sensor

The quantum noise of light fundamentally limits optical phase sensors. A semiclassical picture attributes this noise to the random arrival time of photons from a coherent light source such as a laser. An engineered source of squeezed states suppresses this noise and allows sensitivity beyond the standard quantum limit (SQL) for phase detection. Advanced gravitational wave detectors like LIGO have already incorporated such sources, and nascent efforts in realizing quantum biological measurements have provided glimpses into new capabilities emerging in quantum measurement. We need ways to engineer and use quantum light within deployable quantum sensors that operate outside the confines of a lab environment. Here we present a photonic integrated circuit fabricated in thin-film lithium niobate that provides a path to meet these requirements. We use the second-order nonlinearity to produce a squeezed state at the same frequency as the pump light and realize circuit control and sensing with electro-optics. Using a 26.2 milliwatts of optical power, we measure (2.7 $\pm$ 0.2 )$\%$ squeezing and apply it to increase the signal-to-noise ratio of phase measurement. We anticipate that on-chip photonic systems like this, which operate with low power and integrate all of the needed functionality on a single die, will open new opportunities for quantum optical sensing.Comment: 14 pages, 3+3 figure

Single-Mode Squeezed Light Generation and Tomography with an Integrated Optical Parametric Oscillator

Quantum optical technologies promise advances in sensing, computing, and communication. A key resource is squeezed light, where quantum noise is redistributed between optical quadratures. We introduce a monolithic, chip-scale platform that exploits the $\chi^{(2)}$ nonlinearity of a thin-film lithium niobate (TFLN) resonator device to efficiently generate squeezed states of light. Our system integrates all essential components -- except for the laser and two detectors -- on a single chip with an area of one square centimeter, significantly reducing the size, operational complexity, and power consumption associated with conventional setups. Our work addresses challenges that have limited previous integrated nonlinear photonic implementations that rely on either $\chi^{(3)}$ nonlinear resonators or on integrated waveguide $\chi^{(2)}$ parametric amplifiers. Using the balanced homodyne measurement subsystem that we implemented on the same chip, we measure a squeezing of 0.55 dB and an anti-squeezing of 1.55 dB. We use 20 mW of input power to generate the parametric oscillator pump field by employing second harmonic generation on the same chip. Our work represents a substantial step toward compact and efficient quantum optical systems posed to leverage the rapid advances in integrated nonlinear and quantum photonics.Comment: 21 pages; 4 figures in main body, 8 supplementary figure

Advances in optical materials for large aperture lasers

Lawrence Livermore National Laboratory (LLNL) is using large aperture Nd: glass lasers to investigate the feasibility of inertial confinement fusion. In our experiments high power laser light is focussed onto a small (100 to 500 micron) target containing a deuterium-tritium fuel mixture. During the short (1 to 5 ns) laser pulse the fuel is compressed and heated, resulting in fusion reactions. The generation and control of the powerful laser pulses for these experiments is a challenging scientific and engineering task, which requires the development of new optical materials, fabrication techniques, and coatings. LLNL with the considerable cooperation and support from the optical industry, where most of the research and development and almost all the manufacturing is done, has successfully applied several new developments in these areas

Estimates of array and pool-construction variance for planning efficient DNA-pooling genome wide association studies

<p>Abstract</p> <p>Background</p> <p>Until recently, genome-wide association studies (GWAS) have been restricted to research groups with the budget necessary to genotype hundreds, if not thousands, of samples. Replacing individual genotyping with genotyping of DNA pools in Phase I of a GWAS has proven successful, and dramatically altered the financial feasibility of this approach. When conducting a pool-based GWAS, how well SNP allele frequency is estimated from a DNA pool will influence a study's power to detect associations. Here we address how to control the variance in allele frequency estimation when DNAs are pooled, and how to plan and conduct the most efficient well-powered pool-based GWAS.</p> <p>Methods</p> <p>By examining the variation in allele frequency estimation on SNP arrays between and within DNA pools we determine how array variance [var(e_array)] and pool-construction variance [var(e_construction)] contribute to the total variance of allele frequency estimation. This information is useful in deciding whether replicate arrays or replicate pools are most useful in reducing variance. Our analysis is based on 27 DNA pools ranging in size from 74 to 446 individual samples, genotyped on a collective total of 128 Illumina beadarrays: 24 1M-Single, 32 1M-Duo, and 72 660-Quad.</p> <p>Results</p> <p>For all three Illumina SNP array types our estimates of var(e_array) were similar, between 3-4 × 10^-4for normalized data. Var(e_construction) accounted for between 20-40% of pooling variance across 27 pools in normalized data.</p> <p>Conclusions</p> <p>We conclude that relative to var(e_array), var(e_construction) is of less importance in reducing the variance in allele frequency estimation from DNA pools; however, our data suggests that on average it may be more important than previously thought. We have prepared a simple online tool, PoolingPlanner (available at <url>http://www.kchew.ca/PoolingPlanner/</url>), which calculates the effective sample size (ESS) of a DNA pool given a range of replicate array values. ESS can be used in a power calculator to perform pool-adjusted calculations. This allows one to quickly calculate the loss of power associated with a pooling experiment to make an informed decision on whether a pool-based GWAS is worth pursuing.</p

Evidence for Positive Selection on a Number of MicroRNA Regulatory Interactions during Recent Human Evolution

MicroRNA (miRNA)–mediated gene regulation is of critical functional importance in animals and is thought to be largely constrained during evolution. However, little is known regarding evolutionary changes of the miRNA network and their role in human evolution. Here we show that a number of miRNA binding sites display high levels of population differentiation in humans and thus are likely targets of local adaptation. In a subset we demonstrate that allelic differences modulate miRNA regulation in mammalian cells, including an interaction between miR-155 and TYRP1, an important melanosomal enzyme associated with human pigmentary differences. We identify alternate alleles of TYRP1 that induce or disrupt miR-155 regulation and demonstrate that these alleles are selected with different modes among human populations, causing a strong negative correlation between the frequency of miR-155 regulation of TYRP1 in human populations and their latitude of residence. We propose that local adaptation of microRNA regulation acts as a rheostat to optimize TYRP1 expression in response to differential UV radiation. Our findings illustrate the evolutionary plasticity of the microRNA regulatory network in recent human evolution

The Role of Geography in Human Adaptation

Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme FST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles