Complex Susceptibility Research Articles

Targeting IL-17 in psoriasis: From cutaneous immunobiology to clinical application

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility. Although the hallmark of psoriasis is characterized by cutaneous inflammation and keratinocyte hyperproliferation, recent studies show that the pathologic features observed in psoriasis arises as a result of innate and adaptive immune activation in genetically prone individuals. Studies focused on the microenvironment in the skin of psoriasis lesions have revealed novel cellular and cytokine abnormalities of the immune system. One pathway important is the role of the T(H)17/IL-17 dysregulation. The recent development of biologics that target the IL-17 cytokine pathway has confirmed the importance of T(H)17 and IL-17 homeostasis in the skin and yielded potent therapies in the treatment of psoriasis, and potentially other autoimmune diseases.

Complex genetic susceptibility to vascular dementia and an evidence for its underlying genetic factors associated with memory and associative learning

Genetic basis for vascular dementia (VD) as a typical complex disease has been limitedly reported from association studies conducted with candidate genes. Even recent genomewide association studies (GWAS) could hardly identify additional genetic factors for VD. Although a considerable complexity for its genetic architecture was suspected, there were some challenges to identify false negative associations that resulted from the GWAS. Challenges to identifying genetic factors and their functions after the trials of GWAS revealed that splicing of primary transcript was inhibited (SYK) or delayed (PHLDB2) by a nucleotide substitution of the corresponding gene. The studies gave us the lesson that integrated investigations with statistical genomics as well as functional genomics are needed to identify false negatives from the GWAS. Such endeavors would provide key insights into aspects of underlying nucleotide architectures of VD and incorporate the genetic factors into clinical practice. The recent genetic association studies for susceptibility to VD were briefly overviewed in this article. We also showed a challenge to understanding genetic dissection of VD by a genomic region enrichment analysis with distal cis-regulatory sequences. The analysis with a variant set of potential false negatives from the GWAS revealed that the variants were significantly enriched near genes involved in critical biological processes to VD.

Nonconventional Spin Glass Transition in a Chemically Ordered Pyrochlore

We report on the study of unusual spin glass properties in the geometrically frustrated pyrochlore Tb(2)Mo(2)O(7), T(g) ~/= 24 K. The analysis of the nonlinear part of dc and complex susceptibilities, near the glass transition regime, suggests the existence of a statistical distribution of relaxation times in short-range ordered ferromagnetic clusters. In addition, the magnetic spins are not sufficiently frozen below the glass transition temperature, which is apparently responsible for the nonequilibrium scaling behavior of the static critical exponents of nonlinear susceptibilities. Our report is expected to shed new light in understanding the freezing properties of frustrated pyrochlores with short-range ferromagnetic interactions.

Synthesis and characterization of poly(siloxane–azomethine) iron(III) coordination compounds

Siloxane-containing polyazomethines with linear (PAZ) and cross-linked (CPAZ) architectures and their iron complexes (FePAZ and CFePAZ) have been prepared. The structures of the resulted compounds were investigated by spectral methods (FT-IR, 1H NMR, UV–vis) and electrospray ionization mass spectrometry (ESI-MS). X-ray fluorescence spectrometry was used to determine the Si/Fe ratio and for quantitative analysis of silicon. Paramagnetic susceptibility (χ) and magnetic moment (μ eff) of the soluble iron complex were estimated based on 1H NMR measurements. The iron spin state was determined by Mössbauer spectroscopy, while the electrochemical behavior was studied by cyclic voltammetry. The catalytic activity in hydrogen peroxide decomposition reaction, in alkaline solution was tested. The compound FePAZ proved to increase the dielectric constant of a silicone matrix in which it was incorporated even in very low percent, acting also as an effective plasticizer.

Whole-genome detection of disease-associated deletions or excess homozygosity in a case-control study of rheumatoid arthritis

Unlike genome-wide association studies, few comprehensive studies of copy number variation's contribution to complex human disease susceptibility have been performed. Copy number variations are abundant in humans and represent one of the least well-studied classes of genetic variants; in addition, known rheumatoid arthritis susceptibility loci explain only a portion of familial clustering. Therefore, we performed a genome-wide study of association between deletion or excess homozygosity and rheumatoid arthritis using high-density 550 K SNP genotype data from a genome-wide association study. We used a genome-wide statistical method that we recently developed to test each contiguous SNP locus between 868 cases and 1194 controls to detect excess homozygosity or deletion variants that influence susceptibility. Our method is designed to detect statistically significant evidence of deletions or homozygosity at individual SNPs for SNP-by-SNP analyses and to combine the information among neighboring SNPs for cluster analyses. In addition to successfully detecting the known deletion variants on major histocompatibility complex, we identified 4.3 and 28 kb clusters on chromosomes 10p and 13q, respectively, which were significant at a Bonferroni-type-corrected 0.05 nominal significant level. Independently, we performed analyses using PennCNV, an algorithm for identifying and cataloging copy numbers for individuals based on a hidden Markov model, and identified cases and controls that had chromosomal segments with copy number <2. Using Fisher's exact test for comparing the numbers of cases and controls with copy number <2 per SNP, we identified 26 significant SNPs (protective; more controls than cases) aggregating on chromosome 14 with P-values <10(-8).

An experimental study of magnetic-field and temperature dependence on magnetic fluid’s heating power

This paper firstly presents a measurement system for determining the magnetic properties of magnetic fluids, based on three pickup coils. The accuracy of the system was tested on known samples and then used for the characterization of magnetic losses (heating power P) on the magnetic fluid sample using two different methods. The first method is based on determining the hysteresis loop area and the second on determining the complex susceptibility; and showed that both methods are equivalent. The aim of this paper was to identify the heating power of the liquid at a known value for the magnetic field, and the arbitrary temperature. Thus, we explored the actual reduction in the heating power due to the heating of the sample, which cannot be achieved without the temperature regulated heat bath using established calorimetric methods.

Surgical Treatment of Peripheral Facial Paralysis

The facial nerve passes through the temporal bone and is the longest nerve that travels in a bony canal with a complex course and high susceptibility to injury.When facial nerve becomes swollen from insults such as trauma, inflammation, tumor or iatrogenic injury, its distal

Influence of aging time of oleate precursor on the magnetic relaxation of cobalt ferrite nanoparticles synthesized by the thermal decomposition method

Cobalt ferrite nanoparticles are of interest because of their room temperature coercivity and high magnetic anisotropy constant, which make them attractive in applications such as sensors based on the Brownian relaxation mechanism and probes to determine the mechanical properties of complex fluids at the nanoscale. These nanoparticles can be synthesized with a narrow size distribution by the thermal decomposition of an iron–cobalt oleate precursor in a high boiling point solvent. We studied the influence of aging time of the iron–cobalt oleate precursor on the structure, chemical composition, size, and magnetic relaxation of cobalt ferrite nanoparticles synthesized by the thermal decomposition method. The structure and thermal behavior of the iron–cobalt oleate was studied during the aging process. Infrared spectra indicated a shift in the coordination state of the oleate and iron/cobalt ions from bidentate to bridging coordination. Aging seemed to influence the thermal decomposition of the iron–cobalt oleate as determined from thermogravimmetric analysis and differential scanning calorimetry, where shifts in the temperatures corresponding to decomposition events and a narrowing of the endotherms associated with these events were observed. Aging promoted formation of the spinel crystal structure, as determined from X-ray diffraction, and influenced the nanoparticle magnetic properties, resulting in an increase in blocking temperature and magnetocrystalline anisotropy. Mossbauer spectra also indicated changes in the magnetic properties resulting from aging of the precursor oleate. Although all samples exhibited some degree of Brownian relaxation, as determined from complex susceptibility measurements in a liquid medium, aging of the iron–cobalt oleate precursor resulted in crossing of the in-phase χ′and out-of-phase χ″ components of the complex susceptibility at the frequency of the Brownian magnetic relaxation peak, as expected for nanoparticles that relax through a single relaxation mechanism. The resulting nanoparticles would be suitable for sensors based on the Brownian relaxation mechanism and in determining mechanical properties of complex fluids at the size scale of the nanoparticles.

Estimating the Contributions of Rare and Common Genetic Variations and Clinical Measures to a Model Trait: Adiponectin

Common genetic variation frequently accounts for only a modest amount of interindividual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n = 1,151) and African American (n = 574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (P = 1.16 × 10-(47)) and 47% (P = 5.82 × 10-(20)), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV = 18% (P = 6.40 × 10-(15)) and POV = 5% (P = 0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV = 6% (P = 5.44 × 10-(12)) and POV = 9% (P = 1.44 × 10-(10)), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.

In vitro scan for enhancers at the TCF7L2 locus.

Recent functional characterisations of genome-wide association study (GWAS) loci suggest that cis-regulatory variation may be a common paradigm for complex disease susceptibility. Several studies point to a similar mechanism at the transcription factor 7-like 2 (TCF7L2) GWAS locus for type 2 diabetes. To address this possibility, we carried out an in vitro scan of this diabetes-associated locus to fine-map cis-regulatory sequences within this genomic interval. A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146. In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines. These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.

Mapping cis- and trans-regulatory effects across multiple tissues in twins.

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many eQTL studies typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis-effect on expression cannot be accounted for by common cis-variants, a finding which exposes the contribution of low frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene and identify several replicating trans-variants which act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

Comparison between two culture media for in vitro evaluation of antifungal susceptibility of the Sporothrix schenckii complex

The standard methodology for determining the antifungal sensitivity against the Sporothrix schenckii complex recommends the use of the 1640 Roswell Park Memorial Institute culture medium (RPMI) buffered with morpholinepropanolsulfonic acid (MOPS). However, while this is a high-cost medium which requires a laborious implementation and sterilization by filtration, the Sabouraud dextrose broth is a low-cost medium, widely used in mycology, sterilized by autoclave. To evaluate the performance of the Sabouraud dextrose broth culture medium as a substitute for the RPMI 1640-MOPS in determining the antifungal sensitivity of S. schenckii. Forty-eight clinical isolates were evaluated against five antifungal agents: itraconazole, ketoconazole, fluconazole, amphotericin B and terbinafine, using the method of broth microdilution advocated by the M38-A2 protocol of the Clinical and Laboratory Standards Institute. There were no significant differences between the Minimum Inhibitory Concentrations obtained in the two culture media for all the antifungals, with the exception of the amphotericin B. Regarding this drug, the Minimum Inhibitory Concentration range obtained were wider for the Sabouraud dextrose broth than for the Roswell Park Memorial Institute morpholinepropanelsulfonic acid. The Sabouraud dextrose broth showed potential to be used in the in vitro evaluation of the S. schenckii complex antifungal activity.

Measurement of the dynamics of plasmons inside individual gold nanoparticles using a femtosecond phase-resolved microscope

The selective optical detection of individual metallic nanoparticles (NPs) with high spatial and temporal resolution is a challenging endeavour, yet is key to the understanding of their optical response and their exploitation in applications from miniaturised optoelectronics and sensors to medical diagnostics and therapeutics. However, only few reports on ultrafast pump-probe spectroscopy on single small metallic NPs are available to date. Here, we demonstrate a novel phase-sensitive four-wave mixing (FWM) microscopy in heterodyne detection to resolve for the first time the ultrafast changes of real and imaginary part of the dielectric function of single small (<40nm) spherical gold NPs. The results are quantitatively described via the transient electron temperature and density in gold considering both intraband and interband transitions at the surface plasmon resonance. This novel microscopy technique enables background-free detection of the complex susceptibility change even in highly scattering environments and can be readily applied to any metal nanostructure.

Three Cyanide-Bridged One-Dimensional Single Chain CoIII-MnIIComplexes: Rational Design, Synthesis, Crystal Structures and Magnetic Properties

Two pyridinecarboxamide dicyanidecobalt(III) building blocks and two mononuclear seven-coordinated macrocycle manganese(II) compounds have been rationally selected to assemble cyanide-bridged heterobimetallic complexes, resulting in three cyanide-bridged <TEX>$Co^{III}-Mn^{II}$</TEX> complexes. Single X-ray diffraction analysis show that these complexes <TEX>$\{[Mn(L^1)][Co(bpb)]\}ClO_4{\cdot}CH_3OH{\cdot}0.5H_2O$</TEX> (<TEX>$\mathbf{1}$</TEX>), <TEX>$\{[Mn(L^2)][Co(bpb)]\}ClO_4{\cdot}0.5CH_3OH$</TEX> (<TEX>$\mathbf{2}$</TEX>) and <TEX>${[Mn(L^1)][Co(bpb)]\}ClO_4{\cdot}H_2O$</TEX> (<TEX>$\mathbf{3}$</TEX>) (<TEX>$L^1$</TEX> = 3,6-diazaoctane-1,8-diamine, <TEX>$L^2$</TEX> = 3,6-dioxaoctano-1,8-diamine; <TEX>$bpb2^{2-}$</TEX> = 1,2-bis(pyridine-2-carboxamido)benzenate, <TEX>$bpmb2^{2-}$</TEX> = 1,2-bis(pyridine-2-carboxamido)-4-methyl-benzenate) all present predictable one-dimensional single chain structures. The molecular structures of these one-dimensional complexes consists of alternating units of <TEX>$[Mn(L)]^{2+}$</TEX> (<TEX>$L=L^1$</TEX> or <TEX>$L^2$</TEX>) and <TEX>$[Co(L^{\prime})(CN)2]^-$</TEX> (<TEX>$L^{\prime}=bpb2^{2-}$</TEX>, or <TEX>$bpmb2^{2-}$</TEX>), forming a cyanide-bridged cationic polymeric chain with free <TEX>$ClO_4{^-}$</TEX> as the balance anion. The coordination geometry of manganese(II) ion in the three one-dimensional complexes is a slightly distorted pentagonal-bipyrimidal with two cyanide nitrogen atoms at the trans positions and <TEX>$N_5$</TEX> or <TEX>$N_3O_2$</TEX> coordinating mode at the equatorial plane from ligand <TEX>$L^1$</TEX> or <TEX>$L^2$</TEX>. Investigation over magnetic properties of these complexes reveals that the very weak magnetic coupling between neighboring Mn(II) ions connected by the diamagnetic dicyanidecobalt(III) building block. A best-fit to the magnetic susceptibility of complex <TEX>${\mathbf}{1}$</TEX> leads to the magnetic coupling constants <TEX>$J=-0.084(3)cm^{-1}$</TEX>.

From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases

Celiac disease is characterized by a chronic inflammatory reaction in the intestine and is triggered by gluten, a constituent derived from grains which is present in the common daily diet in the Western world. Despite decades of research, the mechanisms behind celiac disease etiology are still not fully understood, although it is clear that both genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by genome-wide association studies. These have uncovered a wealth of information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in celiac disease, focusing on the “non-HLA” genes. We also present novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms.

Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis?

Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome-wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants. Overall, 502 AS patients were examined, consisting of 312 patients who had first-degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK-Oxford cohort. The frequencies of AS susceptibility loci in IL-23R, IL1R2, ANTXR2, ERAP-1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag single-nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size. HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward higher frequency in the multiplex cases (P = 0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined. HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS.

Paradigm Shift or Shifting Paradigm for Type 1 Diabetes

The age of onset of type 1A diabetes is now immunologically predictable (1). Either because of a lack of sufficient understanding of the pathogenesis of type 1A (immune-mediated) diabetes or a lack of effective therapeutics directed at relevant pathogenic pathways (or both), we cannot yet prevent this disease (2). The article by Liu et al. (3) in this issue of Diabetes addresses both issues in a rat model of autoimmune diabetes (Lew.1WR1). In this genetically susceptible model, multiple viral infections or a viral RNA chemical mimic (poly-IC) activate the innate immune system leading to insulitis and β-cell destruction (4). The viruses do not appear to target islets; rather, they act by inducing inflammation such that anti-inflammatory therapy (e.g., prednisone) at the time of infection prevents diabetes (5). This model was discovered when the Kilham rat virus spontaneously infected a colony of “normal” rats with major histocompatibility complex (MHC) and dominant diabetes susceptibility loci on chromosome 4 ( Iddm 14 ) (6). The iddm14 locus encompasses the family of T-cell receptor Vβ segment genes, and in particular, a specific Vβ13 haplotype is associated with diabetes susceptibility (7). Specific T cells can be targeted by monoclonals to their Vβ sequences to prevent disease. Liu et al. analyzed the percentage and sequences of T cells with Vβ13 in islets of the rat model described above and tested whether a monoclonal antibody to Vβ13 could prevent diabetes. T cells …

Subnatural linewidths in two-photon excited-state spectroscopy

We investigate, theoretically and experimentally, absorption on an excited-state atomic transition in a thermal vapor where the lower state is coherently pumped. We find that the transition linewidth can be sub-natural, i.e. less than the combined linewidth of the lower and upper state. For the specific case of the 6P_{3/2} -> 7S_{1/2} transition in room temperature cesium vapor, we measure a minimum linewidth of 6.6 MHz compared with the natural width of 8.5 MHz. Using perturbation techniques, an expression for the complex susceptibility is obtained which provides excellent agreement with the measured spectra.

IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

ObjectiveThe first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these...

The Evaluation of Susceptibility of Mycobacterium tuberculosis complex Isolates against Primer Antituberculosis Drugs

The Evaluation of Susceptibility of Mycobacterium tuberculosis complex Isolates against Primer Antituberculosis Drugs