Combination of two physical phenomena, capillary pressure gradient and wettability gradient, allows a simple two-step fabrication process that yields a reliable hydrophobic self-cleaning condenser surface. The surface is fabricated with specific microscopic topography and further treatment with a chemically inert low-surface-energy material. This process does not require growth of nanofeatures (nanotubes) or hydrophilic-hydrophobic patterning of the surface. Trapezoidal geometry of the microfeatures facilitates droplet transfer from the Wenzel to the Cassie state and reduces droplet critical diameter. The geometry of the micropatterns enhances local coalescence and directional movement for droplets with diameter much smaller than the radial length of the micropatterns. The hydrophobic self-cleaning micropatterned condenser surface prevents liquid film formation and promotes continuous dropwise condensation cycle. Upon dropwise condensation, droplets follow a designed wettability gradient created with micropatterns from the most hydrophobic to the least hydrophobic end of the surface. The surface has higher condensation efficiency, due to its directional self-cleaning property, than a plain hydrophobic surface. We explain the self-actuated droplet collection mechanism on the condenser surface and demonstrate experimentally the creation of an effective wettability gradient over a 6 mm radial distance. In spite of its fabrication simplicity, the fabricated surface demonstrates self-cleaning property, enhanced condensation performance, and reliability over time. Our work enables creation of a hydrophobic condenser surface with the directional self-cleaning property that can be used for collection of biological (chemical, environmental) aerosol samples or for condensation enhancement.
Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-? (TGF-?) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-? is expressed in a latent form that requires activation. The integrin ?v?8 (encoded by the itgb8 gene) is a receptor for latent TGF-? and is essential for its activation. Expression of integrin ?v?8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human ?v?8 (B5) inhibited TGF-? activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-? activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that ?v?8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity ?v?8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-? pathway to treat fibroinflammatory airway diseases.
Context: A number of small data sets have suggested a potential role for skewed X chromosome activation (XCI), away from the expected 50:50 parent of origin ratio, as an explanation for the strong female preponderance seen in the common autoimmune thyroid diseases (AITD), Graves disease (GD), and Hashimotos thyroiditis (HT). Objective: The objective of the study was to confirm a role for XCI skewing as a potential explanation for the strong female preponderance seen in AITD. Design: The design of the study was to screen XCI in the largest GD, HT, and control case-control cohort and family cohort to date and undertake a meta-analysis of previous AITD XCI reports. Setting: The study was conducted at a research laboratory. Patients: Three hundred and nine GD, 490 HT, and 325 female UK Caucasians controls, 273 UK Caucasian GD families, and a meta-analysis of 454 GD, 673 HT, and 643 female Caucasian controls were included in the study. Main Outcome Measures: Case-control and family-based association studies and meta-analysis were measured. Results: Skewed XCI was observed with GD [odds ratio (OR) 2.17 [95% confidence interval (CI) 1.43-3.30], P = 2.1 × 10(-4)] and a trend toward skewing with HT (P = .08) compared with the control cohort. A meta-analysis of our UK data and that of four previous non-UK Caucasian studies confirmed significant skewing of XCI with GD [OR 2.54 (95% CI 1.58-4.10), P = 1.0 × 10(-4), I(2) = 30.2%] and HT [OR 2.40 (95% CI 1.10-5.26), P = .03, I(2) = 74.3%]. Conclusions: Convincing evidence exists to support a role for skewed XCI in female subjects with AITD, which may, in part, explain the strong female preponderance observed in this disease.
Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.
A novel system was developed to acquire synchronous echocardiography, electrocardiography (EKG), and seismocardiography (SCG) data. The system was developed to facilitate the study of the relationship between the mechanical and electrical characteristics of the heart. The system has both a hardware and software component. The hardware component consists of an application-specific device designed and built to acquire both SCG and EKG signals simultaneously. The software component consists of a package developed to record and synchronize data from both the device and a clinical ultrasound machine. A feasibility test was performed by simultaneous acquisition of a synchronous dataset from a human subject.
The autoimmune thyroid diseases (AITD) include Graves disease (GD) and Hashimotos thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.
The detection of volatile organic compounds (VOCs) in the gas phase by mass-sensitive disk microresonators is reported. The disk resonators were fabricated using a CMOS-compatible silicon micromachining process and subsequently placed in an amplifying feedback loop to sustain oscillation. Sensing of benzene, toluene, and xylene was conducted after applying controlled coatings of an analyte-absorbing polymer. An analytical model of the resonators chemical sensing performance was developed and verified by the experimental data. Limits of detection for the analytes tested were obtained, modeled, and compared to values obtained from other mass-sensitive resonant gas sensors.
The thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1.
The Fc receptor-like 3 (FCRL3) molecule, involved in controlling B-cell signalling, may contribute to the autoimmune disease process. Recently, a genome-wide screen detected association of neighbouring gene FCRL5 with Graves disease (GD). To determine whether FCRL5 represents a further independent B-cell signalling GD susceptibility loci, we screened 12 tag SNPs, capturing all known common variation within FCRL5, in 5192 UK Caucasian GD index cases and controls.
A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves disease (GD), identified nine novel possible regions of association with GD. We used a case-control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case-Control Consortium study group, minor differences in allele frequencies (P>or=10(-3)) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P=0.042-0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases.
Behçets disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçets disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçets disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.
Previous genome-wide microsatellite screening in Graves disease (GD) has suggested several regions of linkage to disease. Although replication has been inconsistent, some regions such as chromosome 5q31-33 have been associated with several Oriental GD patient cohorts. Recently, two studies have reported association of single-nucleotide polymorphism (SNP) rs31480 in interleukin 3 (IL-3) and the rs1368408 and SNP75 (-623 approximately -622 AG/-T) SNPs in secretoglobulin family 3a member 2 (SCGB3A2) with GD and suggested that this may account for linkage to the 5q31-33 region in Oriental GD datasets. We sought to confirm this association in a large Caucasian U.K. GD cohort.
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Although autoantibody production is a key feature of autoimmunity, it is not known whether variation in autoantibody production and clearance pathways is involved in disease susceptibility. The Fc Gamma Receptor IIa (FcGRIIa) molecule is involved in the clearance of autoantibodies and a functional single nucleotide polymorphism (SNP), rs1801274, which has been shown to alter autoantibody clearance, has been associated with a number of autoimmune diseases (AIDs) including systemic lupus erythematosus and type 1 diabetes. This study aimed to determine whether FcGRIIa is associated with Graves disease (GD) in the UK Caucasian population by Tag SNP screening common polymorphisms within the FcGRIIa region.
A novel technique is developed to cancel the effect of environmental parameters, e.g., temperature and humidity, in resonant mass sensing. Utilizing a single resonator, the environmental cancellation is achieved by monitoring a pair of resonant overtones and the effective sensed mass in those overtones. As an eminent advantage, especially compared to dual-mode temperature compensation techniques, the presented technique eliminates any need for previously measured look-up tables or fitting the measurement data. We show that a resonant cantilever beam is an appropriate platform for applying this technique, and derive an analytical expression to relate the actual and effective sensed masses on a cantilever beam. Thereby, it is shown that in applying the presented technique successfully, the effective sensed masses must not be the same in the investigated pair of resonance overtones. To prove the feasibility of the proposed technique, flexural resonance frequencies of a silicon cantilever are measured before and after loading with a strip of photoresist. Applying the presented technique shows significant reductions in influence of environmental parameters, with the temperature and humidity coefficients of frequency being improved from -19.5 to 0.2 ppm degrees C(-1) and from 0.7 to -0.03 ppm %RH(-1), respectively.
A new method for eliminating the noise effect in interpreting the measured magnitude transfer characteristic of a resonator, in particular in extracting the Q-factor, is proposed and successfully tested. In this method the noise contribution to the measured power spectral density of resonator is iteratively excluded through a sequence of least-square curve fittings. The advantage of the presented method becomes more tangible when the signal to noise power ratio (SNR) is close to unity. A set of experiments for a resonant cantilever vibrating at different amplitudes has shown that when SNR is less than 10, the calculation results of conventional methods in extracting the Q-factor, i.e., the 3 dB bandwidth and single least-square curve fit, exhibit significant deviations from the actual Q-factor, while the result of the proposed iterative method remains in 5% margin of error even for a SNR of unity. This method is especially useful when no specific data is available about the measurement noise, except the assumption that the noise spectral density is constant over the measured bandwidth.
Graves disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.
The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.
Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimotos thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.
Seismocardiography (SCG), a representation of mechanical heart motion, may more accurately determine periods of cardiac quiescence within a cardiac cycle than the electrically derived electrocardiogram (EKG) and, thus, may have implications for gating in cardiac computed tomography. We designed and implemented a system to synchronously acquire echocardiography, EKG, and SCG data. The device was used to study the variability between EKG and SCG and characterize the relationship between the mechanical and electrical activity of the heart. For each cardiac cycle, the feature of the SCG indicating Aortic Valve Closure was identified and its time position with respect to the EKG was observed. This position was found to vary for different heart rates and between two human subjects. A color map showing the magnitude of the SCG acceleration and computed velocity was derived, allowing for direct visualization of quiescent phases of the cardiac cycle with respect to heart rate.
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