The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely ...understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.
As the number of bacterial genomes increases dramatically, the demand for easy to use tools with transparent functionality and comprehensible output for applied comparative genomics grows as well. We ...present BlAst Diagnostic Gene findEr (BADGE), a tool for the rapid prediction of diagnostic marker genes (DMGs) for the differentiation of bacterial groups (e.g. pathogenic / nonpathogenic). DMG identification settings can be modified easily and installing and running BADGE does not require specific bioinformatics skills. During the BADGE run the user is informed step by step about the DMG finding process, thus making it easy to evaluate the impact of chosen settings and options. On the basis of an example with relevance for beer brewing, being one of the oldest biotechnological processes known, we show a straightforward procedure, from phenotyping, genome sequencing, assembly and annotation, up to a discriminant marker gene PCR assay, making comparative genomics a means to an end. The value and the functionality of BADGE were thoroughly examined, resulting in the successful identification and validation of an outstanding novel DMG (fabZ) for the discrimination of harmless and harmful contaminations of Pediococcus damnosus, which can be applied for spoilage risk determination in breweries. Concomitantly, we present and compare five complete P. damnosus genomes sequenced in this study, finding that the ability to produce the unwanted, spoilage associated off-flavor diacetyl is a plasmid encoded trait in this important beer spoiling species.
Background Hay fever or seasonal allergic rhinitis (AR) is a chronic disorder associated with IgE sensitization to grass. The underlying genetic variants have not been studied comprehensively. There ...is overwhelming evidence that those who have older siblings have less AR, although the mechanism for this remains unclear. Objective We sought to identify common genetic variant associations with prevalent AR and grass sensitization using existing genome-wide association study (GWAS) data and to determine whether genetic variants modify the protective effect of older siblings. Method Approximately 2.2 million genotyped or imputed single nucleotide polymorphisms were investigated in 4 large European adult cohorts for AR (3,933 self-reported cases vs 8,965 control subjects) and grass sensitization (2,315 cases vs 10,032 control subjects). Results Three loci reached genome-wide significance for either phenotype. The HLA variant rs7775228, which cis -regulates HLA-DRB4 , was strongly associated with grass sensitization and weakly with AR ( Pgrass = 1.6 × 10−9 ; PAR = 8.0 × 10−3 ). Variants in a locus near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32) , which was previously associated with atopic dermatitis and eczema, were also strongly associated with both phenotypes (rs2155219; Pgrass = 9.4 × 10−9 ; PAR = 3.8 × 10−8 ). The third genome-wide significant variant was rs17513503 (Pgrass = 1.2 × 10−8 ; PAR = 7.4 × 10−7 ) which was located near transmembrane protein 232 (TMEM232) and solute carrier family 25, member 46 ( SLC25A46 ). Twelve further loci with suggestive associations were also identified. Using a candidate gene approach, where we considered variants within 164 genes previously thought to be important, we found variants in 3 further genes that may be of interest: thymic stromal lymphopoietin ( TSLP ), Toll-like receptor 6 ( TLR6 ) and nucleotide-binding oligomerization domain containing 1 ( NOD1/CARD4 ). We found no evidence for variants that modified the effect of birth order on either phenotype. Conclusions This relatively large meta-analysis of GWASs identified few loci associated with AR and grass sensitization. No birth order interaction was identified in the current analyses.
We report on hollow shell-shell nanogels with two polymer shells that have different volume phase transition temperatures. By means of small angle neutron scattering (SANS) employing contrast ...variation and molecular dynamics (MD) simulations we show that hollow shell-shell nanocontainers are ideal systems for controlled drug delivery: The temperature responsive swelling of the inner shell controls the uptake and release, while the thermoresponsive swelling of the outer shell controls the size of the void and the colloidal stability. At temperatures between 32 °C < T < 42 °C, the hollow nanocontainers provide a significant void, which is even larger than the initial core size of the template, and they possess a high colloidal stability due to the steric stabilization of the swollen outer shell. Computer simulations showed, that temperature induced switching of the permeability of the inner shell allows for the encapsulation in and release of molecules from the cavity.
Medication non-adherence in heart failure (HF) leads to increased mortality, morbidity and healthcare costs. However, no study has investigated HF patients’ post-hospitalization medication ...non-adherence in Switzerland.
Our primary aim was to assess the prevalence of post-discharge medication non-adherence in patients with HF. A secondary objective was to identify differences between fully and partially adherent patients regarding selected unplanned therapy-related inpatient/outpatient cardiology visits.
A non-experimental cross-sectional study was applied. The prevalence of medication adherence was assessed with a German-translated version of the Medication Adherence Report Scale (MARS-5) and analyzed descriptively. Differences between adherent and partially adherent patients’ numbers of medications, dosing per day and 180-day unplanned inpatient stays or cardiology outpatient visits were explored.
Of 153 recruited patients, 72 participated in the survey. Of these, 26.4 % were not fully adherent. Their most common reason was forgetfulness (23.7 %). There were no significant group differences regarding therapy-related variables or 180-day unplanned cardiology stays/visits.
Considering that over one-quarter of surveyed HF patients were not fully medication adherent, Swiss cardiology nurses need to be sensitized to this issue and trained in adherence-enhancing interventions. Reaching acceptable adherence levels in patients with HF will require further research and action.
The investigation of the response kinetics of smart colloidal microgel films is crucial for their optimization to enable advanced applications. We study the classical thermoresponsive microgel model ...system N-isopropylacrylamide cross-linked with N,N′-methylenebisacrylamide. Without the typically used polyelectrolyte coating of the substrate, thin microgel films are prepared in a single spin-coating step. Atomic force microscopy measurements reveal an extremely dense packing, resulting in a homogeneous compact thin film of microgel particles. The hydration kinetics of these films in H2O and D2O atmospheres as well as the kinetics of the solvent exchange between both water species are investigated with in situ time-of-flight neutron reflectometry (TOF-NR) and in situ Fourier-transform infrared (FTIR) spectroscopy. With accounting for a nonconstant humid atmosphere, the intrinsic diffusion dynamics of water molecules into the thin microgel film are modeled and the specific time constant τ and the effective Flory–Huggins interaction parameter χeff are determined. Comparing the results in H2O and D2O atmospheres, TOF-NR and FTIR spectroscopy results show an increased affinity of the microgel films toward H2O as compared to D2O. From the FTIR spectroscopy data, we further identify different kinetics of intermolecular processes and order them according to their temporal evolution.
Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and ...function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the antiinflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required.
The subunit composition of postsynaptic non-NMDA-type glutamate receptors (GluRs) determines the function and trafficking of the receptor. Changes in GluR composition have been implicated in the ...homeostasis of neuronal excitability and synaptic plasticity underlying learning. Here, we imaged GluRs in vivo during the formation of new postsynaptic densities (PSDs) at Drosophila neuromuscular junctions coexpressing GluRIIA and GluRIIB subunits. GluR composition was independently regulated at directly neighboring PSDs on a submicron scale. Immature PSDs typically had large amounts of GluRIIA and small amounts of GluRIIB. During subsequent PSD maturation, however, the GluRIIA/GluRIIB composition changed and became more balanced. Reducing presynaptic glutamate release increased GluRIIA, but decreased GluRIIB incorporation. Moreover, the maturation of GluR composition correlated in a site-specific manner with the level of Bruchpilot, an active zone protein that is essential for mature glutamate release. Thus, we show that an activity-dependent, site-specific control of GluR composition can contribute to match pre- and postsynaptic assembly.
In this study, we have synthesised small aqueous zwitterionic microgels as model systems for amphoteric microgels. Zwitterions exhibit special behaviour due to defined distance between the opposite ...charges and provide a possibility to incorporate an identical number of positive and negative charges in microgels. Microgels decorated with zwitterionic groups exhibit unique properties compared with their analogues functionalized with separately incorporated oppositely charged co-monomers. In this work, two series of zwitterionic microgels with
N
-isopropylacrylamide (NIPAm) and
N
-vinylcaprolactam (VCL) as main monomers and various amounts of 3-(methacryloylamino)propyldimethyl(3-sulfopropyl) ammonium hydroxide (referred to as sulfobetaine) as zwitterionic co-monomer have been prepared. We investigated the effect of zwitterionic co-monomer content on the swelling behaviour, particle size, size distribution and volume phase transition temperature of the NIPAm-co-sulfobetaine microgels using various scattering methods, as dynamic and static light scattering and small-angle X-ray/neutron scattering. We found a decrease of particle size with the amount of sulfobetaine in the presence of sodium dodecylsulfate, which is contrary to results published earlier by Das et al. (Chem Mater 20: 7157–7163,
2008
) for a similar system of zwitterionic microgels. The decrease of particle size is related to co-surfactant behaviour of sulfobetaine in mixtures with sodium dodecylsulfate. The incorporation of sulfobetaine also increases the polydispersity of the microgels and broadens the volume phase transition.
Second hand tobacco smoke (SHS) and overweight/obesity are risk factors for asthma and lower airway respiratory symptoms. We investigated whether SHS or overweight/obesity were also associated with ...allergic or non-allergic rhinitis.
Cross-sectional data were obtained during the second SAPALDIA Study. Interviewer administered questionnaires were completed by 8047 participants from 8 communities in Switzerland. Blood was collected from 5841 participants and tested for allergen specific IgE. Allergic rhinitis was defined as nasal symptoms with detectable IgE. Data were analysed by multinomial logistic regression with four outcome categories defined according to the presence or absence of rhinitis and/or atopy.
The prevalence of allergic rhinitis was 885 (15.2%) and non-allergic rhinitis 323 (5.5%). The risk of allergic rhinitis was increased in subjects with physician diagnosed asthma (Relative Risk Ratio 6.81; 95%CI 5.39, 8.6), maternal atopy (1.56; 1.27, 1.92) and paternal atopy (1.41; 1.11, 1.79). Older subjects were at lower risk (0.96; 0.95,0.97 per year), as were those raised on a farm (0.64; 0.49,0.84), with older siblings (0.92; 0.86,0.97 per sib) or from rural areas. The risk of non-allergic rhinitis was also increased in subjects with physician diagnosed asthma (4.02; 2.86, 5.67), reduced in males (0.59; 0.46, 0.77), but not associated with upbringing on a farm or older siblings. There were no significant associations of SHS or overweight/obesity with either form of rhinitis.
Allergic and non-allergic rhinitis have different risk factors apart from asthma. There are significant regional variations within Switzerland, which are not explained by the factors examined.
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