Publications

A mid-infrared sensor for label-free on-chip chemical detection was developed using an engineered nanofluidic channel consisting of a Si-liquid-Si slot-structure. A sensitivity with 75 times improvement was achieved compared to conventional evanescent-wave sensing. Mid-infrared spectroscopy is a detection technique commonly used for identifying biochemicals and tracing of toxic molecules, and is free of target labels and sensor surface functionalization. The use of mid-IR spectrum circumvents the need for labeling the sample, because the characteristic wavelength of absorption by many functional groups present in chemical or biological molecules falls within this region of the spectrum. Herein, we present a new chip-scale optofluidic device that utilizes mid-IR techniques for label-free and surface functionalization-free chemical sensing. The optofluidic platform is built using CMOS processes, and is capable of accomplishing broad mid-IR spectral sensing. Fig. 1 schematically illustrates the structure of the mid-IR opto-nanofluidic device. The sensing element is a nanofluidic-channel slot-waveguide with its two ends connected to Si-SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> -Si slot-waveguides. We embed the entire nanofluidic channel and part of the silicon-oxide slot-waveguides in the PDMS chamber. Upon filling the interior of the chamber with liquid analyte, the solution inside the nanofluidic channel converts the fluid-filled channel into a fluidic slot-waveguide. The mid-IR probe light, after passing through the nanofluidic channel, propagates into the second SiO2 slot-waveguide at the other end. The transmitted light is encoded with the absorption spectrum of the analyte in the fluid because the absorption of probe light by the analyte that fills the nanofluidic channel heavily modulates the intensity of the guided light at the characteristic absorption wavelengths. The enhancement of chemical sensitivity of our fluidic slot-waveguide is evaluated. Fig. 2 (a) compares the predicted optical-field profiles for propagating mid-IR (? = 3.3 μm) radiation within a rectangular-strip waveguide, to that of a nanofluidic slot waveguide. In the case of the rectangular strip-waveguide, the optical field is mainly retained inside the Si core and its penetration as an evanescent wave into the surrounding fluid is small. In the slot-waveguide the optical field is highly concentrated at the center of the fluidic channel and interacts strongly with the liquid inside the channel. Thus, even a slight change in the concentration of analyte will result in a significant modulation of intensity to the guided mid-IR that consequently boosts the sensitivity when sensing chemicals. From the plot in Fig. 2 (b), the enhancement-factor Sslot/Sstrip rises to 75 times as the slot-width narrows to d = 80 nm.

This paper describes a method for depositing proteins and cells selectively into microwells fabricated in poly(dimethylsiloxane)an elastomeric organic polymer. The arrays of microwells were generated using soft lithography. The surface between the wells was coated with bovine serum albumin, and the surface within the wells was coated with fibronectin (FN)an adhesive extracellular matrix protein. Fluorescence staining of FN using antibodies indicated that the protein had adsorbed to the wells selectively. Exposure of the FN-coated wells to a suspension of bovine capillary endothelial cells resulted in attachment and spreading of the cells only in the wells. This method for patterning cells was demonstrated with wells of several diameters (≤100 μm) and depths (≤50 μm). It should be useful for (i) the development of sensors based on arrays of cells, (ii) screening combinatorial libraries of ligands on cells, and (iii) testing the effect on cells of compounds and samples relevant to problems in environmental chemistry, pharmacology, medicinal chemistry, research biology, and biodefense.

This paper describes the relationship between the rates of charge transport (by tunneling) across self-assembled monolayers (SAMs) in a metal/SAM//Ga2O3/EGaIn junction and the geometric contact area (Ag) between the conical Ga2O3/EGaIn top-electrode and the bottom-electrode. Measurements of current density, J(V), across SAMs of decanethiolate on silver demonstrate that J(V) increases with Ag when the contact area is small (Ag < 1000 μm2), but reaches a plateau between 1000 and 4000 μm2, where J(0.5 V) ≈ 10–0.52±0.10 A/cm2. The method used to fabricate Ga2O3/EGaIn electrodes generates a tip whose apex is thicker and rougher than its thin, smoother sides. When Ag is small, the Ga2O3/EGaIn electrode contacts the bottom-electrode principally over this rough apex and forms irreproducible areas of electrical contact. When Ag is large, the contact is through the smoother regions peripheral to the apex and is much more reproducible. Measurements of contact pressure between conical EGaIn electrodes and atomic force microscope cantilevers demonstrate that the nominal contact pressure (governed by the mechanical behavior of the oxide skin) decreases approximately inversely with the diameter of geometric contact. This self-regulation of pressure prevents damage to the SAM and makes the ratio of electrical contact area to geometric footprint approximately constant.

The X chromosome (chrX) represents one potential source for the “missing heritability” for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-value = 2.71×10−9, and rs1751138 near ITM2A, P-value = 3.03×10−10) and one for fasting insulin (rs139163435 in Xq23, P-value = 5.18×10−9). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-value = 0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits.

A mid-infrared (mid-IR) spectrometer for label-free on-chip chemical sensing was developed using an engineered nanofluidic channel consisting of a Si-liquid-Si slot-structure. Utilizing the large refractive index contrast (Δn ∼ 2) between the liquid core of the waveguide and the Si cladding, a broadband mid-IR lightwave can be efficiently guided and confined within a nanofluidic capillary (≤100 nm wide). The optical-field enhancement, together with the direct interaction between the probe light and the analyte, increased the sensitivity for chemical detection by 50 times when compared to evanescent-wave sensing. This spectrometer distinguished several common organic liquids (e.g., n-bromohexane, toluene, isopropanol) accurately and could determine the ratio of chemical species (e.g., acetonitrile and ethanol) at low concentration (<5 μL/mL) in a mixture through spectral scanning over their characteristic absorption peaks in the mid-IR regime. The combination of CMOS-compatible planar mid-IR microphotonics, and a high-throughput nanofluidic sensor system, provides a unique platform for chemical detection.

Abstract Affinity capillary electrophoresis (ACE) is a technique that is used to measure the binding affinity of receptors to neutral and charged ligands. ACE experiments are based on differences in the values of electrophoretic mobility of free and bound receptor. Scatchard analysis of the fraction of bound receptor, at equilibrium, as a function of the concentration of free ligand yields the dissociation constant of the receptor‐ligand complex. ACE experiments are most conveniently performed on fused silica capillaries using a negatively charged receptor (molecular mass &lt; 50 kDa) and increasing concentrations of a low molecular weight, charged ligand in the running buffer. ACE experiments that involve high molecular weight receptors may require the use of running buffers containing zwitterionic additives to prevent the receptors from adsorbing appreciably to the wall of the capillary. This review emphasizes ACE experiments performed with two model systems: bovine carbonic anhydrase II (BCA II) with arylsulfonamide ligands and vancomycin (Van), a glycopeptide antibiotic, with D ‐Ala‐ D ‐Ala ( D A D A)‐based peptidyl ligands. Dissociation constants determined from ACE experiments performed with charged receptors and ligands can often be rationalized using electrostatic arguments. The combination of differently charged derivatives of proteins ‐ protein charge ladders ‐ and ACE is a physical‐organic tool that is used to investigate electrostatic effects. Variations of ACE experiments have been used to estimate the charge of Van and of proteins in solution, and to determine the effect of the association of Van to Ac 2 K D A D A on the value of p K a of its N ‐terminal amino group.

It is of interest to compare measures of association of binary traits among samples of bivariate data. One example is the comparison of association within a sample of monozygotic (MZ) twins to that within a sample of dizygotic (DZ) twins. A larger association in the MZ twins suggests that the trait of interest may have a genetic component. The Bivariate data in this example are binary traits for the twins in each pair. Another example is the comparison of a measure of Hardy-Weinberg disequilibrium across several populations. The bivariate data in this example are the two alleles comprising the genotype of interest. We propose using derived logistic regression equations from the full exponential model for the bivariate outcomes to test for homogeneity. We adjust for correlation among outcomes via generalized estimating equations. This modeling approach allows for adjustment for individual-level and pair-level covariates and thereby allows for testing for gene × environment interactions. Further, we extend the model to allow for simultaneous analysis of two diseases, which allows for testing for a genetic component to the coaggregation of two diseases. In contrast to approaches proposed by previous authors, no special software is required; our approach can be easily implemented in standard software packages. We compare our results to those of other methods proposed in the literature for data from the Vietnam Era Twins Study. We apply our methods also to the Anqing Twin Study and to data on major depression and generalized anxiety disorder from the Virginia Twin Register. Genet. Epidemiol. 20:228–238, 2001. © 2001 Wiley-Liss, Inc.

Background Coronary artery disease is a leading cause of morbidity and mortality in the United States. Coronary artery disease can lead to major complications including myocardial infarction (MI). The association of dietary cholesterol with coronary artery disease remains inconsistent. We examined the relation of dietary cholesterol with the incidence of MI among participants of the Million Veteran Program. Methods and Results The Million Veteran Program is a prospective cohort database collecting genetic and nongenetic factors influencing chronic diseases. We analyzed data from 180 156 veterans with complete information on relevant dietary intake. The association between dietary cholesterol and MI risk was assessed using both linear and nonlinear models. Statistical significance was determined using the Wald test for linear trends and the likelihood ratio test for nonlinearity, alongside comparisons between high (≥300 mg/d) and low (&lt;300 mg/d) cholesterol intake groups. In this study of 180 156 veterans with mean follow‐up of 3.5 years, we observed a linear, dose–response association between dietary cholesterol intake and risk of MI, with every 100‐mg/d increment in cholesterol intake associated with a 5% higher MI risk (relative risk [RR], 1.05 [95% CI, 1.02–1.08]). Subjects consuming &gt;300 mg/d of cholesterol had a 15% increased MI risk compared with those consuming less (RR, 1.15 [95% CI, 1.06–1.25]). Conclusions We found that dietary cholesterol intake was linearly associated with greater risk of MI. These findings contribute to the growing literature highlighting the impact dietary cholesterol has on cardiovascular health. Reductions in cholesterol intake, which can be achieved by decreasing the intake of meat and eggs, may reduce the risk of incident MI.

Background Alexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period. Methods Participants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated. Results BMI was significantly and positively associated with TAS-20 score (p<0.0001, both at 31 years and at 46 years of ages). The association remained statistically significant after adjustment for potential confounders (sex, marital status and several socio-economic indicators). In individuals who experienced the greatest change in BMI (in either direction) over the 15-year period, there was a modest mean increase in TAS-20 score. Conclusions Our data revealed that TAS-20 score was correlated with and co-varied with body mass status. We suggest that future clinical research should consider the role of alexithymia in obesity. Further investigation of this relationship is warranted to ensure that the needs of obese subjects with undiagnosed alexithymia are considered in the design of weight management programmes.