In particular, the consensus scoring procedure improves prediction of binding energies, which is the greatest problem in virtual screening. Selleck Vemurafenib Although the obtained binding energy predictions are still inaccurate and further development

is required before they can be used for this purpose in routine lead optimization, the consensus scoring procedure is at present the only alternative for improvement of the in silico screening procedure. Wang & Wang (2001) distinguished three main ranking methods of consensus scoring for virtual screening: rank-by-number (all the candidates are ranked according to the average predicted values given by all the scoring functions), rank-by-rank (all the candidates are ranked by the average ranks predicted by all the involved scoring functions) and rank-by-vote (if a candidate is predicted to be on the top, for example 2%, by a certain scoring function,

then it gets a ‘vote’ from that scoring function; the final score of a candidate compound is the number of votes gathered from all the scoring functions, which may range from 0 to the total number of scoring functions). Tyrosine Kinase Inhibitor Library The approach we applied may be treated as a modification of rank-by-number method, as we used a sum of total score by Surflex and a doubled value of fit obtained with the Screen Library module of discovery studio 2.1. Although most of the proposed hits are characterized by lipophilicity <2 (the range for CNS active drugs is from 2 to 4) and do not cross blood–brain barrier easily, it is obvious that they should be treated as prototypes of drugs that require further optimization (especially of their ADMET properties) before reaching the market. The studies performed allowed 15 potential inhibitors to be selected from the database of 1 161 000 compounds, which constitutes the reasonable alternative for experimental HTS procedure. Moreover, novel structural features of JEV NS3 helicase/NTPase have been identified,

including new important residues in the enzyme-binding pocket. The problem of anti-JEV specificity of novel compounds and their selectivity over human ATPases was also addressed. To conclude, the computational project performed may be treated as a guide for experimental Edoxaban work on viral helicases/NTPases and antiviral drug design. Calculations were performed under a computational grant by the Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw, Poland, grant number G30-18. “
“T-cell help is essential for CTL-memory formation. Nevertheless, it is unclear whether the continuous presence of CD4+ T-helper (Th) cells is required during dendritic cell (DC)/CD8+ T-cell encounters, or whether a DC will remember the helper signal after the Th cell has departed. This question is relevant for the design of therapeutic cancer vaccines. Therefore, we investigated how human DCs need to interact with CD4+ T cells to mediate efficient repetitive CTL expansion in vitro.

Heligmosomoides polygyrus bakeri is a fascinating intestinal parasitic nematode of mice that was isolated in the 1950s by Ehrenford [1] and since then has attracted increasing attention from researchers, particularly in the last two decades and especially from parasite immunologists. H. p. bakeri represents an important model of chronic helminth infection and is phylogenetically related to the ruminant parasites Haemonchus contortus NVP-BEZ235 ic50 and Teladorsagia circumcincta and the human hookworms Ancylostoma duodenale and Nector americanus

[2]. The parasite has played an important role in helping us to explore and understand many different aspects of infection with helminths, but its pre-eminence is its capacity to cause long-lasting chronic infections in its murine host [3, 4]. Unlike other rodent

intestinal nematodes that became popular laboratory models in the 1960s (e.g. Nippostrongylus brasiliensis, Trichuris muris, Trichinella spiralis, Strongyloides ratti [5, 6]) and which cause limited infections (although note that in some mouse strains, T. muris may develop to patency and cause chronic infections [7, 8]), often restricted selleck inhibitor to 2–3 weeks, and induce strong acquired immunity in their hosts, H. p. bakeri is able to survive for up to 10 months in many commonly used laboratory mouse strains [3, 4]. It is this capacity to cause long-lasting chronic infections

in mice that distinguishes H. p. bakeri from other intestinal nematodes and which makes it a convenient model of chronic nematode infections in humans and our domestic animals [9-12]. This capacity of H. p. bakeri to survive for so long, without inducing rapid expulsion, is facilitated by the mechanisms that this species uses to downregulate local intestinal immune responses primarily in its immediate vicinity, but also in more distant host tissues [13-15]. H. p. bakeri is known to secrete immunomodulatory factors Resminostat (IMF) that interfere with both the induction and expression of mucosal immune responses [12, 16-18], and one consequence of this is that other parasites residing in the intestinal tract (and elsewhere in host tissues) of concurrently infected animals can benefit by sustaining longer infections than would otherwise be the case. The prolongation of infections with other species has been demonstrated in the laboratory [19-22] and has been detected in the field in wild rodent populations naturally infected with the close relative H. p. polygyrus [23, 24]. The literature on H. p. bakeri is large and has been complicated by taxonomic problems centring on the relationships of H. p. bakeri with another closely related parasite of wild rodents in Europe, which is now more correctly referred to as H. p. polygyrus.

This threshold could be numerical or physiological, Apoptosis Compound Library cell line or a combination of both. It therefore takes a “team effort” to cause periodontitis in that the disease requires cooperative

interactions among bacteria with different roles. A recently formulated model that accommodates these concepts is called the polymicrobial synergy and dysbiosis (PSD) model [2]. This model holds that physiologically compatible organisms assemble into heterotypic communities, which exist in a controlled immunoinflammatory state. While they are pro-inflammatory and can produce toxic products such as proteases, overgrowth and overt pathogenicity are controlled by the host response. The microbial constituents of the communities can vary among individuals, among sites, and over time. Colonization by keystone pathogens such as P.

gingivalis elevates the virulence of the entire community following interactive communication with accessory pathogens. Initially, host immune surveillance is impaired and the dysbiotic community increases in number. Subsequently, the community proactively induces inflammation to sustain itself with derived nutrients, which will also shape a modified “inflammophilic” community. The action of pathobionts in the community, in addition to overt pathogens, eventually leads to destruction of periodontal tissues. The PSD model reconciles a number of features of periodontal Selleckchem SB431542 disease that were discordant with earlier concepts of pathogenicity. These include: the variable microbiota at disease sites, even within the same patient; the presence of pathogens

in the absence of disease; the episodic nature of the disease; and the failure of P. gingivalis to cause periodontitis in the absence of the commensal microbiota [13]. Bacteria on human mucosal surfaces tend to accumulate into complex multispecies communities, a process controlled by a sophisticated series of interbacterial signaling and host response interactions. Within these communities, bacteria have specialized roles, such as provision of an essential enzyme for progressive nutrient metabolism. Bacteria Verteporfin that influence the pathogenicity of the entire community are keystone pathogens, the best-documented example of which is P. gingivalis. While P. gingivalis can affect gene and protein expression in other community members, the major keystone-related influence of the organism is likely through interference with host immunity. This is accomplished by a multipronged approach that compromises immune function on a number of levels (Fig. 1 and 3). It is important to bear in mind, however, that periodontitis is an inflammatory disease, and thus the timing, location, and context of immune suppression by P. gingivalis will have major significance for the ultimate progression of disease.

Chromosome conformation capture experiments suggest the production of unique chromosomal loops in peripheral B cells anchored by Eμ and 3′RR physical interactions 19, 20. In the case of CSR, recruitment check details and transcription of the switch-acceptor region in close proximity to the switch μ donor region (switch–switch synapsis) might be promoted by the 3′RR itself 19. Combined mutations of both the Eμ and 3′RR would be the most appropriate tool to address this issue. Ongoing recombination and mutation during B-cell development make the IgH locus a hotspot for translocation. Many lymphomas are marked by proto-oncogene translocation into the IgH locus (Fig. 2A). Bcl-2 and cyclin

D1 translocations, found respectively in follicular and mantle cell lymphoma, take place during the V(D)J recombination 21, 22. The cyclin D1, cyclin D3 or c-maf translocations often observed in myelomas are obviously linked to CSR 23. However c-myc translocation, a typical hallmark of Burkitt lymphoma, PLX3397 is related to either SHM or CSR 24. Among IgH cis-regulatory elements, Eμ was expected to be the critical c-myc deregulator in lymphomagenesis. However, Eμ-c-myc transgenic mice expressed c-myc in B-cell

progenitors and, thus, developed an immature form of lymphoma 25 that differed from human Burkitt lymphoma tumors that harbor a mature B-cell signature 24. In Burkitt lymphoma, c-myc translocation

breakpoints occur either in the V(D)J (endemic Burkitt lymphoma) or in switch regions (sporadic Burkitt lymphoma), both of which keep the 3′RR intact. Thus, transgenic models confirm that the 3′RR is a good candidate for oncogene deregulation (Fig. 2B). c-myc-3′RR transgenics developed Burkitt lymphoma-like Pyruvate dehydrogenase proliferation within a few months 26 and similarly, the knock-in of a 3′RR cassette upstream of the endogenous c-myc gene induced B-cell lymphomas 27. Interestingly, the phenotype of lymphoproliferation induced by the c-myc-3′RR transgene varied with the genetic background. C57Bl/6 animals developed Burkitt-like lymphoma 26, while no lymphoproliferation occurred when the c-myc-3′RR transgene was bred in a Balb/c background (known to harbor a polymorphism of p16Ink4a) 28. p16Ink4a is an inhibitor of cyclin-dependent kinase (Cdk)-4, a regulatory protein implicated in the first steps of cell cycle entry. Breeding c-myc-3′RR C57Bl/6 animals in a Cdk4R24C mutant background (a dominant Cdk4 oncogene resistant to inhibition by p16Ink4a and other members of the Ink family 29) resulted in susceptibility to mantle cell lymphoma (Vincent-Fabert et al., submitted). A convincing demonstration of the essential contribution of the 3′RR in lymphomagenesis has been produced by transgenic models of B-cell lymphomas with IgH-c-myc translocations 30.

The FTDC criteria reached a sensitivity of 93% for

possible and 80% for probable bvFTD. Early-onset cases displayed significantly more disinhibition, loss of empathy and compulsive behavior with respect to late-onset bvFTD leading to a slightly higher sensitivity of the diagnostic criteria (97% vs 91%). There were no differences in the diagnostic performance between tau-positive and tau-negative cases. In subjects clinically diagnosed as IWR-1 manufacturer bvFTD, a “possible bvFTD” diagnosis reached a positive predictive value for FTLD pathology of 90%, irrespective of underlying proteinopathy. False-positive clinical diagnoses were mainly Alzheimer’s disease. These cases were significantly older, had less family history of dementia and had a predominantly apathetic clinical picture. The revised bvFTD criteria present good sensitivity and positive predictive value in both early

and late-onset cases and regardless of the underlying FTLD pathology. “
“Probably all neuropathologists know this dilemma: on the one hand, they have extremely precious archival material in their possession, which has buy Cabozantinib been collected over many years from many different laboratories. Typically, this material is extremely well characterized, and often, it contains especially significant tissue specimens from unique cases. On the other hand, they face severe scepticism when they plan to use this archival material for large-scale gene expression studies by microarray analysis, since previous handling in the absence of RNA protection, prolonged storage at room temperature, and fixation with formaldehyde may dramatically reduce the amount of retrievable RNA. Fortunately, this dilemma can be solved. We give here examples from enough our own, multiple sclerosis-centered laboratory and explain why archival tissue might be more authentic for the disease process and might yield more information about the molecular and cellular substrates driving CNS inflammation in MS patients than more recently acquired tissues. “
“Granular cell tumor (GCT) of the spine is uncommon, with intradural extramedullary location being exceptionally rare. The non-specific

clinical presentation and variable histologic patterns can make recognition of this tumor challenging. Two previous reports of GCT of the spine were reviewed (Medline 1960–2009) and analyzed with respect to this case report. The patients included two women and one man (mean age, 28.7 years). Patients presented with 3 to 4 months of lower back pain and/or lower extremity radiculopathy. The lesions appeared radiographically to be intradural and extramedullary or intramedullary. The tumors were found at T10 or L1-L2 space. Radiographically, all tumors enhanced homogenously on T1 post-gadolinium imaging with a mean tumor size of approximately 1.6 cm. Histologically, the tumors were composed of large, polygonal granular cells.

[37] Collectively, these studies demonstrate that iron uptake from ferrioxamine is mediated through the reductase/permease system.[37, 38] More recently, we were

able to identify the FOB1 and FOB2 as two closely related genes that encode cell surface proteins involved in binding ferrioxamine to R. oryzae cell surface.[39] Attenuation of expression of these two genes results in compromising the ability of R. oryzae to take up iron from ferrioxamine in vitro and reduces virulence in a deferoxamine-treated mouse model of mucormycosis.[40] A hallmark of mucormycosis is the universal propensity of the infection to invade blood vessels.[1] The Mucorales angioinvasion capabilities likely contribute to the capacity of the organisms to haematogenously disseminate to Selleckchem Olaparib other target organs. Therefore, interactions of invading organisms with endothelial cells and extracellular matrix proteins lining blood vessels represent a critical step in the progression of the disease. Earlier studies demonstrated the ability of Mucorales to bind U0126 in vitro to extracellular

laminin and type IV collagen[41] as well as human umbilical vein endothelial cells.[42] Moreover, Mucorales appear to damage endothelial cells in vitro via a mechanism that involves the induction of their own endocytosis by the mammalian cells.[42] This endocytosis process is mediated by the binding of Mucorales to a mammalian Glucose Regulated Protein with the molecular weight of 78 kDa (GRP78).[43] Interestingly, only germlings of R. oryzae

bind to GRP78 and not spores, thereby fitting the notion that germlings are likely responsible for the haematogenous dissemination Phosphoprotein phosphatase during mucormycosis. Thus far in fungal infection, GRP78 appears to be a unique host cell receptor since neither Candida nor Aspergillus bind to this protein during invasion of host tissues.[43] GRP78 is a heat shock protein that is mainly found in the endoplasmic reticulum acting as a chaperon for facilitating proper protein folding and targeting misfolded proteins for proteosome degradation.[44] It also plays an important role in endoplasmic reticulum Ca2+ homeostasis and in serving as a sensor for stress.[45] Finally, GRP78 was reported to be antiapoptotic and plays critical cytoprotective roles in early embryogenesis, oncogenesis, neurodegenerative diseases and atherosclerosis.[46] Fitting with the concept of GRP78 being a stress-related protein is the finding that GRP78 is overexpressed on the host cell surface when endothelial cells exposed to elevated concentrations of glucose and iron consistent with those seen during hyperglycaemia and DKA. This elevated GRP78 expression results in increased ability of R. oryzae to invade and damage endothelial cells in a receptor-dependent manner.[43] More recently, the Mucorales ligand that binds to GRP78 was identified as the spore coat protein homologs (CotH).

Alternatively, these observations may be indicative of differences in subjects’ agonal states. In conclusion, these results demonstrate that in AD hippocampus, UBL immunoreactivity increases in the neuronal nucleoplasm and is associated with region-specific neurofibrillary changes. Up-regulation of UBL could contribute to pathology progression, or reflect a compensatory Vorinostat mw response. Future

studies examining the link between UBL and NFT as well as other types of AD pathology are warranted. We are indebted to the support of the participants in the ADRC at the University of Pittsburgh. This study was supported by NIH grants NIA AG05133 (University of Pittsburgh ADRC), AG014449 and AG025204 (MDI), The Snee-Reinhardt Charitable Foundation (MDI), and by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (KM). Ms. Suganya Srinivasan,

Ms. Lan Shao, Ms. Natsuko Kato and Ms. Megumi Mitani provided expert technical assistance. “
“We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer’s disease (AD) patients. Therefore, we tried to determine Akt inhibitor the cellular component-dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found

marked decline SB-3CT of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up-regulated around senile plaques, β-amyloid deposition might be associated with astrocytosis through the HGF signaling pathway. “
“Integrins are expressed in tumor cells and tumor endothelial cells, and likely play important roles in glioma angiogenesis and invasion. We investigated the anti-glioma mechanisms of cilengitide (EMD121974), an αvβ3 integrin inhibitor, utilizing the novel invasive glioma models, J3T-1 and J3T-2. Immunohistochemical staining of cells in culture and brain tumors in rats revealed positive αvβ3 integrin expression in J3T-2 cells and tumor endothelial cells, but not in J3T-1 cells. Established J3T-1 and J3T-2 orthotopic gliomas in athymic rats were treated with cilengitide or solvent.

In contrast, in the same cultures, there was abundant IFN-γPos Teff expansion, resulting on day 3 in very low aTreg:aTeff ratios ranging from 0·02

to 1·2 (Fig. 6d). Together, these data provide evidence to suggest that both in vitro and in vivo exposure to IFN-α can potentially cause an unbalanced generation of activated Teffs at the expense of Treg activation. The maintenance of immune homeostasis relies on the co-existence of different cell types with unique and sometimes divergent functions, which are co-ordinately activated to achieve initial effector functions in response to pathogens and subsequent immune inactivation after pathogen clearance. However, the mechanisms that Fulvestrant research buy define the sequential activation/expansion of effector and regulatory cells are still incompletely understood. In this study, we focused on the potential role of IFN-I in controlling the dynamic balance between Treg and Teff activation during polyclonal T-cell activation in human PBMC. The main findings in the study are that (i) anti-CD3 activation of PBMC induces prominent FoxP3 expression on CD4+ cells and the generation of two major subtypes of FoxP3+ cells, CD4+ FoxP3HI IFN-γNeg IL-2Neg aTregs and CD4+ FoxP3Low/Neg IFN-γPos IL-2Pos aTeffs; (ii) IFN-I, buy NVP-LDE225 either exogenously added or endogenously generated by double-stranded

RNA stimulation or from plasma of patients with SLE, limits the generation of aTregs, (iii) IFN-α (but not IFN-β) favours Teff expansion, leading to a reduced aTreg:aTeff ratio; (iv) inhibition of IL-2 production during T-cell activation is a potential mechanism involved in IFN-α-induced suppression of aTreg induction; and (v) the in vivo exposure to IFN-α tilts the balance between aTregs and aTeffs towards Teff upon ex vivo expansion of PBMC. Taken together, these findings provide evidence C-X-C chemokine receptor type 7 (CXCR-7) to suggest that, by inhibiting Treg activation and proliferation, the transient IFN-α production in response to a viral infection may co-ordinate the sequential generation of

aTeffs and aTregs, and that the Teff:Treg balance may be altered under conditions of chronic IFN-α stimulation. A potential role of IFN-α in controlling the dynamic generation of regulatory T cells in vivo, both in humans and in mice, is supported by different observations. (i) The transient period of immunosuppression that follows the recovery of primary viral infections coincides with the decline in the production of IFN-I and an increase in the number of Tregs;22,23 (ii) when measles virus is introduced into a mouse deficient in the IFNα/β receptor, this results in significantly higher numbers of Tregs;40 (iii) in vivo treatment of mice with poly(I:C) leads to a decrease in the number of Tregs,41 and (iv) chronic disorders characterized by persistent IFN-α stimulation are frequently associated with low numbers of Tregs and with autoimmunity.

The cells were analysed by flow cytometry on a FACSCanto II (BD Biosciences) using FACS Diva software. Specificity of signal was determined by inhibition of staining using purified AID (AICDA, Dundee Cell Products) or A3G (Immunodiagnostics Inc.). Where cells were double-labelled for AID and A3G a monoclonal antibody (mAb) to A3G (Immunodiagnostics Inc.) was used and the secondary antibodies were FITC anti-goat immunoglobulin (Sigma-Aldrich) and a phycoerythrin-conjugated anti-mouse immunoglobulin antibody

(Southern Biotechnology Associates, Birmingham, AL). To detect A3G 10 × 106 cells were lysed in 1 ml RIPA buffer for 30 min on ice, cleared by centrifugation and equal volume of 2 × SDS sample buffer was added under reducing conditions before SDS–PAGE. After I BET 762 transfer of proteins to a PVDF membrane, Western blotting was carried out with mouse mAb to A3G (#7105; ImmunoDiagnostics) and β-actin (clone AC-15; Sigma), using horseradish peroxidase-conjugated anti-mouse IgG antibody and Immobilon Western HRP Substrate (Millipore, Watford, UK). About 5 × 106 B cells were harvested and washed with PBS, before extraction of RNA with the Promega SV Total RNA Isolation System. RNA was reverse transcribed according to the manufacturer’s instructions with oligo(dT) primers

and AMV reverse transcriptase (Promega, Southampton, UK). Real-time PCR with cDNA as template this website was performed with Sigma’s SYBR Green JumpStart Taq Ready Mix (Sigma-Aldrich) tuclazepam and gene-specific primers for A3G (5′-TTGTTGCCCGCCTCTACTAC-3′, 5′-TTGGCTGTACACGAA CTTGC-3′), AID (5′-AGAGGCGTGACAGTGCTACA-3′, 5′-TGTAGCGGAGGAAG AGC AAT-3′) and glyceraldehyde 3-phosphate dehydrogense

(GAPDH: 5′-CTTTTGCGTCGCCAGCCGAG-3′, 5′-ACCAGGCGCCC AATACGACC-3′) as housekeeping control. A Corbett Rotor-Gene 6000 PCR cycler was used to run the reactions and manufacturer’s software to analyse data with the ‘Two Standard Curve’ method. The resulting data were normalized to the housekeeping gene GAPDH and expressed relative to unstimulated cells which were accorded an arbitrary value of 100. To determine the concentrations of CD40L + IL-4 that will induce optimum AID and A3G mRNA relative to unstimulated cells, these were titrated from 50 to 200 ng/ml CD40L and 20–100 units/ml IL-4. The results suggested that 100 U/ml IL-4 with 100 ng/ml CD40L were most consistent in eliciting AID and A3G. The effect of AID expression was examined in isolated CD19+ B cells by flow cytometry analysis for cell surface IgM, IgG and IgA isotypes using the following fluorochrome-conjugated mAbs: anti-IgG-FITC and anti-IgM-phycoerythrin (BD Pharmingen, Oxford, UK), anti-IgE-FITC and anti-IgA-FITC (Miltenyi Biotec; Bisley, Surrey, UK).

It has been shown that the addition of erythrocytes to cultured slanDC blocks their capacity

to produce IL-12 and TNF-α via the interaction of CD47 on erythrocytes and the corresponding ligand signal regulatory protein α on slanDC.4 After slanDC leave the bloodstream and infiltrate the tissue, as it was shown in inflamed skin of AD lesions, the control by erythrocytes is lost. Our study suggests that histamine might take over this control function in the tissue because we could show that histamine reduces the highly pro-inflammatory capacity of slanDC, particularly via activation of the H4R. To be sure that histamine stimulation does not reduce cytokine production in general, we investigated IL-10 as a X-396 supplier cytokine INCB024360 supplier that is associated with anti-inflammatory actions. Interleukin-10 reduces the production of IL-2, TNF-α, IFN-γ and co-stimulatory molecules and was shown to counteract the inflammatory response in allergic contact dermatitis.24 In our study we could not observe a significant effect of histamine receptor activation on the release of IL-10. As a result, it can be assumed that H4R and H2R stimulation on slanDC specifically down-regulate the production of the pro-inflammatory mediators TNF-α and IL-12, whereas the level of the anti-inflammatory mediator IL-10 is not affected. The differential regulation of cytokine release by histamine might

be explained by varying signalling processes involved. For example, it was shown that the activation of mitogen-activated protein kinase signalling mediates histamine-induced down-regulation of IL-12p70 in monocytes,15 but on the other hand induces IL-10 production in monocytes.25 Our observations fit the current understanding

of the role of the H4R on antigen-presenting cells. Several studies have shown that the H4R on DC has an anti-inflammatory role: on MoDC, monocytes and inflammatory dendritic epidermal cells the production of IL-12 and CCL2 was down-regulated after H4R activation.15–17 In response to the reduced presence of these mediators, PJ34 HCl Th1 polarization is impaired and a lower number of macrophages and T cells is attracted to the site of the immune response, respectively. We can draw the conclusion that the stimulation of the H4R on DC, and as shown here in particular on slanDC, could greatly reduce the inflammatory responses taking place in the course of inflammatory skin diseases like AD and H4R agonists therefore might represent potential therapeutic tools in these kinds of diseases. This study was supported by grants from the Deutsche Forschungsgemeinschaft DFG: Gu434/5-1 and GRK1441/1 and the European Community (COST action BM0806). Maria Gschwandtner was supported by a grant from the Hannover Biomedical Research School. The authors declare no conflict of interest.