Tfg (Trk fused gene) is a Carma-1/IKKgamma interacting protein involved in CD40-induced canonical NF-KB signaling

Carma-1 is required for B cell receptor-/CD40- and T cell receptor-/CD28-induced B- and T-cell activation via JNK and NF-betaB. In B cells, Carma-1 becomes phosphorylated by PKCbeta, leading to its oligomerization. Subsequent Bcl10 binding induces IKKbeta-activation and, thereby, canonical NF-KB signalling. Despite these findings it is still unknown how exactly Carma-1 is connected to the plasma membrane and to the IKK-complex. Therefore, we purified Carma-1 complexes from mouse CH12 B cells using anti-Carma-1 affinity columns. Mass spectrometric analyses of the column eluates demonstrated the presence of Carma-1 as well as three previously uncharacterized adaptor proteins in B cells, one of which was the Trk-fused gene (Tfg), an adaptor protein containing PB1 and coiledcoil domains. Whereas Tfg was originally identified as fusion partner of oncogenic Trk tyrosine kinase mutants, the normal cellular homologue of Tfg has so far not been described in B cells. However, Tfg has been shown in other systems to interact with IKKgamma and to enhance TNFinduced NF-KB activation. Tfg and Carma-1 co-localized at the plasma membrane and perinuclear structures in B cells. We further corroborated the interactions of Tfg, IKKgamma and Carma-1 by Blue Native gel electrophoresis, where Carma-1 and Tfg formed a 0.7–1 MDa complex. Ectopic expression of Tfg increased the molecular mass of IKKgamma complexes, fused IKKgamma, Bcl10 and Carma-1 complexes to a ~2 MDa complex, and increased basal and CD40-induced canonical activity of NF-KB and IKKbeta. In contrast, shRNA-mediated silencing of Tfg decreased CD40-induced IKKbeta activity. Very interestingly, in primary B cells, highest expression of Tfg was detected in marginal zone and B1 B cells, and Carma-1 and Tfg formed complexes in these B cells. Since Carma-1 is required for marginal zone B cell and B1 B cell development, we suggest that a functional interaction between Carma-1 and Tfg contributes to development and maintenance of these cells by means of canonical NF-KB signals

Pictures of Synthetic Biology: A reflective discussion of the representation of Synthetic Biology (SB) in the German-language media and by SB experts

This article is concerned with the representation of Synthetic Biology in the media and by biotechnology experts. An analysis was made of German-language media articles published between 2004 and 2008, and interviews with biotechnology-experts at the Synthetic Biology conference SB 3.0 in Zurich 2007. The results have been reflected in terms of the definition of Synthetic Biology, applications of Synthetic Biology and the perspectives of opportunities and risks. In the media, Synthetic Biology is represented as a new scientific field of biology with an engineering-like thinking, while the scientists interviewed mostly define Synthetic Biology as contrary to nature and the natural system. Media articles present Synthetic Biology broadly with positive potential and inform the publics less about the potential risks than about the benefits of Synthetic Biology. In contrast, the experts interviewed reflect more on the risks than the opportunities of Synthetic Biology. Both used metaphors to describe Synthetic Biology and its aspects

Quality of life and surgical outcome of ABBA versus EndoCATS endoscopic thyroid surgery: a single center experience

BACKGROUND Thyroid surgery is often performed, especially in young female patients. As patient satisfaction become more and more important, different extra-cervical \textquotedblremote\textquotedbl approaches have evolved to avoid visible scars in the neck for better cosmetic outcome. The most common remote approaches are the transaxillary and retroauricular. Aim of this work is to compare Endoscopic Cephalic Access Thyroid Surgery (EndoCATS) and axillo-bilateral-breast approach (ABBA) to standard open procedures regarding perioperative outcome and in addition to control cohorts regarding quality of life (QoL) and patient satisfaction. METHODS In a single center, 59 EndoCATS und 52 ABBA procedures were included out of a 2 years period and compared to 225 open procedures using propensity-score matching. For the endoscopic procedures, cosmetic outcome, patient satisfaction and QoL (SF-12 questionnaire) were examined in prospective follow-up. For QoL a German standard cohort and non-surgically patients with thyroid disease were used as controls. RESULT The overall perioperative outcome was similar for all endoscopic compared to open thyroid surgeries. Surgical time was longer for endoscopic procedures. There were no cases of permanent hypoparathyroidism and no significant differences regarding temporary or permanent recurrent laryngeal nerve (RLN) palsies between open and ABBA or EndoCATS procedures (χ2; p = 0.893 and 0.840). For ABBA and EndoCATS, 89.6% and 94.2% of patients were satisfied with the surgical procedure. Regarding QoL, there was an overall significant difference in distribution for physical, but not for mental health between groups (p < 0.001 and 0.658). Both endoscopic groups performed slightly worse regarding physical health, but without significant difference between the individual groups in post hoc multiple comparison. CONCLUSION Endoscopic thyroid surgery is safe with comparable perioperative outcome in experienced high-volume centers. Patient satisfaction and cosmetic results are excellent; QoL is impaired in surgical patients, as they perform slightly worse compared to German standard cohort and non-surgical patients

Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children

BackgroundCombination therapies are frequently recommended as maintenance therapy for people with asthma, whose disease is not adequately controlled with inhaled steroids. Fluticasone/salmeterol (FP/SAL) and budesonide/formoterol (BUD/F) have been assessed against their respective monocomponents, but there is a need to compare these two therapies on a head-to-head basis.ObjectivesTo estimate the relative effects of fluticasone/salmeterol and budesonide/formoterol in terms of asthma control, safety and lung function.Search strategyWe searched the Cochrane Airways Group register of trials with prespecified terms. We performed additional hand searching of manufacturers' web sites and online trial registries. Searches are current to May 2008.Selection criteriaRandomised studies comparing fixed dose FP/SAL and BUD/ F were eligible, for a minimum of 12 weeks. Crossover studies were excluded. Our primary outcomes were: i) exacerbations requiring oral steroid bursts, ii) hospital admission and iii) serious adverse events.Data collection and analysisTwo authors independently assessed studies for inclusion in the review. We combined continuous data outcomes with a mean difference (MD), and dichotomous data outcomes with an odds ratio (OR).Main resultsFive studies met the review entry criteria (5537 participants). Primary outcomes: The odds of an exacerbation requiring oral steroids did not differ significantly between treatments (OR 0.89; 95% CI 0.73 to 1.09, three studies, 4515 participants). The odds of an exacerbation leading hospital admission were also not significantly different (OR 1.29; 95% CI 0.68 to 2.47, four studies, 4879 participants). The odds of serious adverse events did not differ significantly between treatments (OR 1.47; 95% CI 0.75, 2.86, three studies, 4054 participants). Secondary outcomes: Lung function outcomes, symptoms, rescue medication, exacerbations leading ED visit/hospital admission and adverse events were not significantly different between treatments.Authors' conclusionsThe evidence in this review indicates that differences in the requirement for oral steroids and hospital admission between BUD/F and FP/SAL do not reach statistical significance. However, the confidence intervals do not exclude clinically important differences between treatments in reducing exacerbations or causing adverse events. The width of the confidence intervals for the primary outcomes justify further trials in order to better determine the relative effects of these drug combinations. Although this review sought to assess the effects of these drugs in both adults and children, no trials were identified in the under-12s and research in this area is of a high priority

Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study.

BACKGROUND:Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer's disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual's amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer's disease (AD). METHODS:The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. RESULTS:In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. CONCLUSIONS:The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD

Loss spectroscopy of molecular solids: Combining experiment and theory

The nature of the lowest-energy electronic excitations in prototypical molecular solids is studied here in detail by combining electron energy loss spectroscopy (EELS) experiments and state-of-the-art many-body calculations based on the Bethe–Salpeter equation. From a detailed comparison of the spectra in picene, coronene and tetracene we generally find a good agreement between theory and experiment, with an upshift of the main features of the calculated spectrum of 0.1–0.2 eV, which can be considered the error bar of the calculation. We focus on the anisotropy of the spectra, which illustrates the complexity of this class of materials, showing a high sensitivity with respect to the three-dimensional packing of the molecular units in the crystal. The differences between the measured and the calculated spectra are explained in terms of the small differences between the crystal structures of the measured samples and the structural model used in the calculations. Finally, we discuss the role played by the different electron–hole interactions in the spectra. We thus demonstrate that the combination of highly accurate experimental EELS and theoretical analysis is a powerful tool to elucidate and understand the electronic properties of molecular solids

Constant temperature mashing at 72 °C for the production of beers with a reduced alcohol content in micro brewing systems

In this paper, we present a constant temperature mashing procedure where grist made of Pilsner malt is mashed-in directly in the temperature regime of alpha-amylase activity, thus omitting all conventional steps, followed by constant temperature mashing at 72 °C. The aim was to investigate an alternative mashing procedure for the production of alcohol-reduced beers. The mashing proceeds with a rapid buildup of sugars and is completed after 120 min at the latest, giving an iodine normal and clear wort. However, the distribution of the different sugars in the worts is strongly altered, in comparison to a more classical mashing procedure. The free amino nitrogen (FAN) concentration is sufficient for vivid fermentation with the bottom fermenting yeast Saccharomyces pastorianus TUM 34/70. The lag phase and initial fermentation performance of this yeast strain are comparable for conventionally and isothermally (72 °C) mashed wort. Under the given conditions the fermentation of the isothermally (72 °C) made wort is finished after 6 days whereas a conventional wort needs 4–5 days more to be completed. The alcohol concentration is remarkably reduced by isothermal mashing leading to roughly 3.4 vol.-% with an original gravity of 11°P whereas with a conventional mashing procedure 4.4 vol.-% are obtained for the same original gravity. In both cases the concentrations of the fermentation by-products are comparable. A preliminary comparison of tasteand foam stability did not show striking differences. Constant temperature mashing at 72 °C is a simple way to reduce the alcohol content of beer enriching it at the same time with non-fermentable sugars

Effects of Spinal and Peripheral Injection of α1A or α1D Adrenoceptor Antagonists on Bladder Activity in Rat Models with or without Bladder Outlet Obstruction

Purpose Antagonists of α1-adrenergic receptors (α1ARs) relax prostate smooth muscle and relieve voiding and storage symptoms. Recently, increased expression of α1ARs with change of its subtype expression has been proved in bladder outlet obstruction (BOO). To search for the evidence of changes in α1ARs subtype expression and activity in the peripheral and spinal routes, the effects of spinal and peripheral administration of tamsulosin (an α1A/D-selective AR), naftopidil (an α1A/D-selective AR), and doxazosin (non-selective AR) on bladder activity were investigated in a rat model with or without BOO. Methods A total of 65 female Sprague-Dawley rats were divided into the BOO surgery group (n=47) and the sham surgery group (n=18). After 6 weeks, cystometry was assessed before and after intrathecal and intra-arterial administrations of tamsulosin, naftopidil, and doxazosin. Results After intra-arterial administrations of all three drugs, bladder capacity (BC) was increased and maximal intravesical pressure (Pmax) was decreased in both BOO and the sham rat models (P<0.05). After intrathecal administration of all three drugs, BC was increased and Pmax was decreased in only the BOO group. The episodes of involuntary contraction in the BOO rat models were decreased by intra-arterial administration (P=0.031). The increase of BC after intrathercal and intra-arterial administrations of α1ARs was significantly greater in the BOO group than in the sham group (P=0.023, P=0.041). In the BOO group, the increase of BC and decrease in Pmax were greater by intra-arterial administration than by intrathecal administration (P=0.035). There were no significant differences of the degrees of changes in the cystometric parameters among the three different α1ARs. Conclusions Up-regulations of the α1ARs in BOO were observed by the greater increases of BC after α1AR antagonist administrations in the BOO group than in the sham group. However, there were no subtype differences of the α1ARs in functional parameters of bladder activity. In addition, α1ARs also act on the lumbosacral cord which implies that the sensitivity of α1ARs is increased in pathologic models such as BOO. Further evaluation including differential expression of α1ARs in BOO models are need

The Pristine Inner Galaxy Survey (PIGS) VII: a discovery of the first inner Galaxy CEMP-r/s star

Well-studied very metal-poor (VMP, [Fe/H] < -2 ) stars in the inner Galaxy are few in number, and they are of special interest because they are expected to be among the oldest stars in the MilkyWay. We present high-resolution spectroscopic follow-up of the carbon-enhanced metal-poor (CEMP) star Pristine_184237.56-260624.5 (hereafter Pr184237) identified in the Pristine Inner Galaxy Survey. This star has an apocentre of about 2 kpc. Its atmospheric parameters (Teff = 5100 K, log g = 2.0, [Fe/H] = -2.60) were derived based on the non-local thermodynamic equilibrium (NLTE) line formation. We determined abundances for 32 elements, including 15 heavy elements beyond the iron group. The NLTE abundances were calculated for 13 elements from Na to Pb. Pr184237 is strongly enhanced in C, N, O, and both s- and r-process elements from Ba to Pb; it reveals a low carbon isotope ratio of 12C/13C = 7. The element abundance pattern in the Na-Zn range is typical of halo stars. With [Ba/Eu] = 0.32, Pr184237 is the first star of the CEMP-r/s subclass identified in the inner Galaxy. Variations in radial velocity suggest binarity. We tested whether a pollution by the s- or i-process material produced in the more massive and evolved companion can form the observed abundance pattern and find that an i-process in the asymptotic giant branch star with a progenitor mass of 1.0-2.0 Msun can be the solution.Comment: 15 pages, 11 figures, 5 tables, MNRAS, accepte