Modeling the Cumulative Genetic Risk for Multiple Sclerosis from Genome-Wide Association Data

Background: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. Methods: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. Results: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years). Conclusions: The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.Version of Recor

Surveillance of antenatal influenza vaccination: validity of current systems and recommendations for improvement

Abstract Background: Although influenza vaccination is recommended during pregnancy as standard of care, limited surveillance data are available for monitoring uptake. Our aim was to evaluate the validity of existing surveillance in Western Australia for measuring antenatal influenza immunisations. Methods: The self-reported vaccination status of 563 women who delivered between April and October 2013 was compared against three passive data collection sources: a state-wide antenatal influenza vaccination database maintained by the Department of Health, a public maternity hospital database, and a private health service database. Sensitivity, specificity, and positive and negative predictive values were calculated for each system using self-report as the “gold standard.” Results: The state-wide antenatal vaccination database detected 45.7 % (95 % CI: 40.1–51.4 %) of influenza vaccinations, the public maternity hospital database detected 66.7 % (95 % CI: 55.1–76.9 %), and the private health service database detected 29.1 % (95 % CI: 20.5–39.4 %). Specificity exceeded 90 % and positive predictive values exceeded 80 % for each system. Sensitivity was lowest for women whose antenatal care was provided by a private obstetrician. Conclusions: Existing resources for surveillance of antenatal influenza vaccinations detect 29–67 % of vaccinations. Considering the importance of influenza immunisation as a public health intervention, particularly in pregnant women, improvements to routine monitoring of influenza vaccination is warranted

Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus

Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with haemagglutinin, causing both disruption of antibody secretion and FluBI B-cell death within 18 h. In mice infected with A/WSN/33, lung-resident FluBI B cells are infected by the virus, thus delaying the onset of protective antibody release into the lungs, whereas FluBI cells in the draining lymph node are not infected and proliferate. We propose that influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response.National Institutes of Health (U.S.

Communicating Phylogeny: Evolutionary Tree Diagrams in Museums

Tree of life diagrams are graphic representations of phylogeny—the evolutionary history and relationships of lineages—and as such these graphics have the potential to convey key evolutionary ideas and principles to a variety of audiences. Museums play a significant role in teaching about evolution to the public, and tree graphics form a common element in many exhibits even though little is known about their impact on visitor understanding. How phylogenies are depicted and used in informal science settings impacts their accessibility and effectiveness in communicating about evolution to visitors. In this paper, we summarize the analysis of 185 tree of life graphics collected from museum exhibits at 52 institutions and highlight some potential implications of how trees are presented that may support or hinder visitors’ understanding about evolution. While further work is needed, existing learning research suggests that common elements among the diversity of museum trees such as the inclusion of anagenesis and absence of time and shared characters might represent potential barriers to visitor understanding

Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin

<p>Abstract</p> <p>Background</p> <p>Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing.</p> <p>Results</p> <p>The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 μg) injected intrathecally produce thermal hyperalgesia. At higher doses (10 μg) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons.</p> <p>Conclusion</p> <p>The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury.</p

Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst

The Na+/K+-ATPase plays a pivotal role during preimplantation development; it establishes a trans-epithelial ionic gradient that facilitates the formation of the fluid-filled blastocyst cavity, crucial for implantation and successful pregnancy. The Na+/K+-ATPase is also implicated in regulating tight junctions and cardiotonic steroid (CTS)-induced signal transduction via SRC. We investigated the expression of SRC family kinase (SFK) members, Src and Yes, during preimplantation development and determined whether SFK activity is required for blastocyst formation. Embryos were collected following super-ovulation of CD1 or MF1 female mice. RT-PCR was used to detect SFK mRNAs encoding Src and Yes throughout preimplantation development. SRC and YES protein were localized throughout preimplantation development. Treatment of mouse morulae with the SFK inhibitors PP2 and SU6656 for 18 hours resulted in a reversible blockade of progression to the blastocyst stage. Blastocysts treated with 10−3 M ouabain for 2 or 10 minutes and immediately immunostained for phosphorylation at SRC tyr418 displayed reduced phosphorylation while in contrast blastocysts treated with 10−4 M displayed increased tyr418 fluorescence. SFK inhibition increased and SFK activation reduced trophectoderm tight junction permeability in blastocysts. The results demonstrate that SFKs are expressed during preimplantation development and that SFK activity is required for blastocyst formation and is an important mediator of trophectoderm tight junction permeability

Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis

Synergy study with chemotherapeutic agents is a common in vitro strategy in the search for effective cancer therapy. For non-chemotherapeutic agents, efficacious synergistic effects are uncommon. Here, we have examined two non-chemotherapeutic agents for synergistic effects: lovastatin and Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) for synergistic effects; on three human malignant glioblastoma cell lines, M059K, M59J, and A172. Cells treated with lovastatin plus TRAIL for 48 h showed 50% apoptotic cell death, whereas TRAIL alone (1,000 ng/ml) did not, suggesting that lovastatin sensitized the glioblastoma cells to TRAIL attack. Cell cycle analysis indicated that lovastatin increased G0–G1 arrest in these cells. Annexin V study demonstrated that apoptosis was the predominant mode of cell death. We conclude that the combination of lovastatin and TRAIL enhances apoptosis synergistically. Moreover, lovastatin sensitized glioblastoma cells to TRAIL, suggesting a new strategy to treat glioblastoma

The Signaller's Dilemma: A Cost–Benefit Analysis of Public and Private Communication

Understanding the diversity of animal signals requires knowledge of factors which may influence the different stages of communication, from the production of a signal by the sender up to the detection, identification and final decision-making in the receiver. Yet, many studies on signalling systems focus exclusively on the sender, and often ignore the receiver side and the ecological conditions under which signals evolve.We study a neotropical katydid which uses airborne sound for long distance communication, but also an alternative form of private signalling through substrate vibration. We quantified the strength of predation by bats which eavesdrop on the airborne sound signal, by analysing insect remains at roosts of a bat family. Males do not arbitrarily use one or the other channel for communication, but spend more time with private signalling under full moon conditions, when the nocturnal rainforest favours predation by visually hunting predators. Measurements of metabolic CO(2)-production rate indicate that the energy necessary for signalling increases 3-fold in full moon nights when private signalling is favoured. The background noise level for the airborne sound channel can amount to 70 dB SPL, whereas it is low in the vibration channel in the low frequency range of the vibration signal. The active space of the airborne sound signal varies between 22 and 35 meters, contrasting with about 4 meters with the vibration signal transmitted on the insect's favourite roost plant. Signal perception was studied using neurophysiological methods under outdoor conditions, which is more reliable for the private mode of communication.Our results demonstrate the complex effects of ecological conditions, such as predation, nocturnal ambient light levels, and masking noise levels on the performance of receivers in detecting mating signals, and that the net advantage or disadvantage of a mode of communication strongly depends on these conditions

Communication in the Third Dimension: Song Perch Height of Rivals Affects Singing Response in Nightingales

Many animals use long-range signals to compete over mates and resources. Optimal transmission can be achieved by choosing efficient signals, or by choosing adequate signalling perches and song posts. High signalling perches benefit sound transmission and reception, but may be more risky due to exposure to airborne predators. Perch height could thus reflect male quality, with individuals signalling at higher perches appearing as more threatening to rivals. Using playbacks on nightingales (Luscinia megarhynchos), we simulated rivals singing at the same height as residents, or singing three metres higher. Surprisingly, residents increased song output stronger, and, varying with future pairing success, overlapped more songs of the playback when rivals were singing at the same height than when they were singing higher. Other than expected, rivals singing at the same height may thus be experienced as more threatening than rivals singing at higher perches. Our study provides new evidence that territorial animals integrate information on signalling height and thus on vertical cues in their assessment of rivals

Structural and functional analysis of cellular networks with CellNetAnalyzer

BACKGROUND: Mathematical modelling of cellular networks is an integral part of Systems Biology and requires appropriate software tools. An important class of methods in Systems Biology deals with structural or topological (parameter-free) analysis of cellular networks. So far, software tools providing such methods for both mass-flow (metabolic) as well as signal-flow (signalling and regulatory) networks are lacking. RESULTS: Herein we introduce CellNetAnalyzer, a toolbox for MATLAB facilitating, in an interactive and visual manner, a comprehensive structural analysis of metabolic, signalling and regulatory networks. The particular strengths of CellNetAnalyzer are methods for functional network analysis, i.e. for characterising functional states, for detecting functional dependencies, for identifying intervention strategies, or for giving qualitative predictions on the effects of perturbations. CellNetAnalyzer extends its predecessor FluxAnalyzer (originally developed for metabolic network and pathway analysis) by a new modelling framework for examining signal-flow networks. Two of the novel methods implemented in CellNetAnalyzer are discussed in more detail regarding algorithmic issues and applications: the computation and analysis (i) of shortest positive and shortest negative paths and circuits in interaction graphs and (ii) of minimal intervention sets in logical networks. CONCLUSION: CellNetAnalyzer provides a single suite to perform structural and qualitative analysis of both mass-flow- and signal-flow-based cellular networks in a user-friendly environment. It provides a large toolbox with various, partially unique, functions and algorithms for functional network analysis.CellNetAnalyzer is freely available for academic use