Association of IFNL3 rs12979860 and rs8099917 with Biochemical Predictors of Interferon Responsiveness in Chronic Hepatitis C Virus Infection

Background & Aims

Genetic variations near the interferon lambda 3 gene (IFNL3, IL28B) are the most powerful predictors for sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection, compared to other biochemical or histological baseline parameters. We evaluated whether the interplay of both IFNL3 polymorphisms rs12979860 and rs8099917 together with non-genetic clinical factors contributes to the predictive role of these genetic variants.

Methods

The cohort comprised 1,402 patients of European descent with chronic HCV type 1 infection. 1,298 patients received interferon-based antiviral therapy, and 719 (55%) achieved SVR. The IFNL3 polymorphisms were genotyped by polymerase chain reaction and melting curve analysis.

Results

A significant correlation was found between the IFNL3 polymorphisms and biochemical as well as virologic predictors of treatment outcome such as ALT, GGT, cholesterol, and HCV RNA levels. In multivariate regression analysis, IFLN3 SNPs, HCV RNA levels, and the GGT/ALT ratio were independent predictors of SVR. Dependent on the GGT/ALT ratio and on the HCV RNA concentration, significant variations in the likelihood for achieving SVR were observed in both, carriers of the responder as well as non-responder alleles.

Conclusions

Our data support a clear association between IFNL3 genotypes and baseline parameters known to impact interferon responsiveness. Improved treatment outcome prediction was achieved when these predictors were considered in combination with the IFNL3 genotype.     

Earliest Evidence for Social Endogamy in the 9,000-Year-Old-Population of Basta,Jordan

The transition from mobile to sedentary life was one of the greatest social challenges of the human past. Yet little is known about the impact of this fundamental change on social interactions amongst early Neolithic communities, which are best recorded in the Near East. The importance of social processes associated with these economic and ecological changes has long been underestimated. However, ethnographic observations demonstrate that generalized reciprocity – such as open access to resources and land – had to be reduced to a circumscribed group before regular farming and herding could be successfully established. Our aim was thus to investigate the role of familial relationships as one possible factor within this process of segregation as recorded directly in the skeletal remains, rather than based on hypothetical correlations such as house types and social units. Here we present the revealing results of the systematically recorded epigenetic characteristics of teeth and skulls of the late Pre-Pottery Neolithic community of Basta in Southern Jordan (Figure S1). Additionally, mobility was reconstructed via a systematic strontium (Sr) isotope analysis of tooth enamel of the Basta individuals. The frequency of congenitally missing maxillary lateral incisors in the 9,000-year-old community of Basta is exceptionally high (35.7%). Genetic studies and a worldwide comparison of the general rate of this dental anomaly in modern and historic populations show that the enhanced frequency can only be explained by close familial relationships akin to endogamy. This is supported by strontium isotope analyses of teeth, indicating a local origin of almost all investigated individuals. Yet, the accompanying archaeological finds document far-reaching economic exchange with neighboring groups and a population density hitherto unparalleled. We thus conclude that endogamy in the early Neolithic village of Basta was not due to geographic isolation or a lack of exogamous mating partners but a socio-cultural choice.     

Analysis of epitope-specific immune responses induced by vaccination with structurally folded and unfolded recombinant Bet v 1 allergen derivatives in man

Previously, we have constructed recombinant derivatives of the major birch pollen allergen, Bet v 1, with a more than 100-fold reduced ability to induce IgE-mediated allergic reactions. These derivatives differed from each other because the two recombinant Bet v 1 fragments represented unfolded molecules whereas the recombinant trimer resembled most of the structural fold of the Bet v 1 allergen. In this study, we analyzed the Ab (IgE, IgG subclass, IgA, IgM) response to Bet v 1, recombinant and synthetic Bet v 1-derived peptides in birch pollen allergic patients who had been vaccinated with the derivatives or adjuvant alone. Furthermore, we studied the induction of IgE-mediated skin responses in these patients using Bet v 1 and Bet v 1 fragments. Both types of vaccines induced a comparable IgG1 and IgG4 response against new sequential epitopes which overlap with the conformational IgE epitopes of Bet v 1. This response was 4- to 5-fold higher than that induced by immunotherapy with birch pollen extract. Trimer more than fragments induced also IgE responses against new epitopes and a transient increase in skin sensitivity to the fragments at the beginning of therapy. However, skin reactions to Bet v 1 tended to decrease one year after treatment in both actively treated groups. We demonstrate that vaccination with folded and unfolded recombinant allergen derivatives induces IgG Abs against new epitopes. These data may be important for the development of therapeutic as well as prophylactic vaccines based on recombinant allergens.     

Rapid screening for soil ecotoxicity with a battery of luminescent bacteria tests

A bacterial test battery, involving i) Microtox, an aquatic test, ii) the Flash assay, a soil-suspension test (with Vibrio fischeri as the test organism), and iii) the Metal Detector assay, a semi-specific aquatic test for heavy metals (with recombinant luminescent Escherichia coli), was used in a combined toxicological and chemical hazard assessment of Estonian soils sampled from a former Soviet military airfield (13 samples) and from traffic-influenced roadsides (5 samples). The soils showed slightly elevated levels of total petroleum hydrocarbons (TPH), but not of heavy metals. In most of the samples, the levels of TPH did not exceed the Estonian permitted limit values set for residential areas. Toxicity testing was performed on both fresh and dried soils, after aqueous extraction for 1 hour and 24 hours. The toxicity results obtained with the Microtox test did not significantly differ in all of the sample treatment schemes; however, it appeared that the drying and sieving of the soils increased the bioavailability of toxicants, probably due to an enlarged reactive soil surface area. According to chemical analysis of the soils and the data from the Microtox test and the Metal Detector assay (performed on aqueous elutriates of the soils), these soils would not be considered to be hazardous. In contrast, the Flash assay performed on soil-water suspensions of dried soils, showed that most of the soils were toxic and thus probably contained undetermined particle-bound bioavailable toxicants. The photobacterial toxicity test (the Flash assay) can be recommended for the rapid screening of soils, as it is sensitive, cheap and inexpensive, and provides valuable information on particle-bound bioavailable toxicants, useful for complementing a chemical analysis and for assessing the risks originating from polluted soils.     

Associations between thyroid hormones and serum metabolite profiles in an euthyroid population

Metabolomics - The aim was to characterise associations between circulating thyroid hormones—free thyroxine (FT4) and thyrotropin (TSH)—and the metabolite profiles in serum samples from...     

Carbon sequestration potential of soils in southeast Germany derived from stable soil organic carbon saturation

Sequestration of atmospheric carbon (C) in soils through improved management of forest and agricultural land is considered to have high potential for global CO₂ mitigation. However, the potential of soils to sequester soil organic carbon (SOC) in a stable form, which is limited by the stabilization of SOC against microbial mineralization, is largely unknown. In this study, we estimated the C sequestration potential of soils in southeast Germany by calculating the potential SOC saturation of silt and clay particles according to Hassink [Plant and Soil 191 (1997) 77] on the basis of 516 soil profiles. The determination of the current SOC content of silt and clay fractions for major soil units and land uses allowed an estimation of the C saturation deficit corresponding to the long‐term C sequestration potential. The results showed that cropland soils have a low level of C saturation of around 50% and could store considerable amounts of additional SOC. A relatively high C sequestration potential was also determined for grassland soils. In contrast, forest soils had a low C sequestration potential as they were almost C saturated. A high proportion of sites with a high degree of apparent oversaturation revealed that in acidic, coarse‐textured soils the relation to silt and clay is not suitable to estimate the stable C saturation. A strong correlation of the C saturation deficit with temperature and precipitation allowed a spatial estimation of the C sequestration potential for Bavaria. In total, about 395 Mt CO₂‐equivalents could theoretically be stored in A horizons of cultivated soils – four times the annual emission of greenhouse gases in Bavaria. Although achieving the entire estimated C storage capacity is unrealistic, improved management of cultivated land could contribute significantly to CO₂ mitigation. Moreover, increasing SOC stocks have additional benefits with respect to enhanced soil fertility and agricultural productivity.     

Inhibition of mTOR down-regulates scavenger receptor,class B,type I (SR-BI) expression,reduces endothelial cell migration and impairs nitric oxide production

The mammalian target of rapamycin (mTOR) inhibiting drug rapamycin (Sirolimus) has severe side effects in patients including hyperlipidemia, an established risk factor for atherosclerosis. Recently, it was shown that rapamycin decreases hepatic LDL receptor (LDL-R) expression, which likely contributes to hypercholesterolemia. Scavenger receptor, class B, type I (SR-BI) is the major HDL receptor and consequently regulating HDL-cholesterol levels and the athero-protective effects of HDL. By using the mTOR inhibitor rapamycin, we show that SR-BI is down-regulated in human umbilical vein endothelial cells (HUVECs). This reduction of SR-BI protein as well as mRNA levels by about 50% did not alter HDL particle uptake or HDL-derived lipid transfer. However, rapamycin reduced HDL-induced activation of eNOS and stimulation of endothelial cell migration. The effects on cell migration could be counteracted by SR-BI overexpression, indicating that decreased SR-BI expression is in part responsible for the rapamycin-induced effects. We demonstrate that inhibition of mTOR leads to endothelial cell dysfunction and decreased SR-BI expression, which may contribute to atherogenesis during rapamycin treatment.     

Microtubule Dynamic Instability Controls Podosome Patterning in Osteoclasts through EB1, Cortactin,and Src

In osteoclasts (OCs) podosomes are organized in a belt, a feature critical for bone resorption. Although microtubules (MTs) promote the formation and stability of the belt, the MT and/or podosome molecules that mediate the interaction of the two systems are not identified. Because the growing “plus” ends of MTs point toward the podosome belt, plus-end tracking proteins (+TIPs) might regulate podosome patterning. Among the +TIPs, EB1 increased as OCs matured and was enriched in the podosome belt, and EB1-positive MTs targeted podosomes. Suppression of MT dynamic instability, displacement of EB1 from MT ends, or EB1 depletion resulted in the loss of the podosome belt. We identified cortactin as an Src-dependent interacting partner of EB1. Cortactin-deficient OCs presented a defective MT targeting to, and patterning of, podosomes and reduced bone resorption. Suppression of MT dynamic instability or EB1 depletion increased cortactin phosphorylation, decreasing its acetylation and affecting its interaction with EB1. Thus, dynamic MTs and podosomes interact to control bone resorption.     

Polymorphisms in glutathione S-transferase are risk factors for perioperative acute myocardial infarction after cardiac surgery: a preliminary study

In the present study we explored glutathione S-transferase (GST) polymorphisms in selected patients who experienced accelerated myocardial injury following open heart surgery and compared these to a control group of patients without postoperative complications. 758 Patients were enrolled from which 132 patients were selected to genotype analysis according to exclusion criteria. Patients were divided into the following groups: Group I: control patients (n = 78) without and Group II.: study patients (n = 54) with evidence of perioperative myocardial infarction. Genotyping for GSTP1 A (Ile105Ile/Ala113Ala), B (Ile105Val/Ala113Ala) and C (Ile105Val/Ala113Val) alleles was performed by using real-time-PCR. The heterozygous AC allele was nearly three times elevated (18.5 vs. 7.7 %) in the patients who suffered postoperative myocardial infarction compared to controls. Contrary, we found allele frequency of 14.1 % for homozygous BB allele in the control group whereas no such allele combination was present in the study group. These preliminary results may suggest the protective role for the B and C alleles during myocardial oxidative stress whereas the A allele may represent predisposing risk for cellular injury in patients undergoing cardiac surgery.