MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS

The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseases and quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS are generally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointly with that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiple phenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linear combination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hidden to single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power in many scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only one phenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen over these. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed, such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing case-control or non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance of MultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these data MultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach, while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associated linear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula, suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritable phenotypes

Immunophenotyping of Circulating T Helper Cells Argues for Multiple Functions and Plasticity of T Cells In Vivo in Humans - Possible Role in Asthma

BACKGROUND: The immune process driving eosinophilic and non-eosinophilic asthma is likely driven by different subsets of T helper (Th) cells. Recently, in vitro studies and animal studies suggest that Th cell subsets displays plasticity by changing their transcription factor or by expressing multiple transcription factors. Our aim was to determine whether individuals with asthma and elevated circulating eosinophils express signs of different regulatory immune mechanisms compared with asthmatics with low blood eosinophils and non-asthmatic control subjects. In addition, determine the relationship between eosinophilia and circulating Th cell subsets. METHODOLOGY/PRINCIPAL FINDINGS: Participants were selected from a random epidemiological cohort, the West Sweden Asthma Study. Immunophenotypes of fresh peripheral blood cells obtained from stable asthmatics, with and without elevated eosinophilic inflammation (EOS high and EOS low respectively) and control subjects, were determined by flow cytometry. No differences in the number of Th1 (T-bet), Th2 (GATA-3), Th17 (RORγt) or Treg (FOXP3) cells were observed between the groups when analysing each subset separately. However, in all groups, each of the Th subsets showed expression of additional canonical transcription factors T-bet, GATA-3, RORγt and FOXP3. Furthermore, by in vitro stimulation with anti-CD3/anti-CD28 there was a significant increase of single expressing GATA-3(+) and co-expressing T-bet(+)GATA-3(+) cells in the EOS high asthmatics in comparison with control subjects. In addition, T-bet(-)GATA-3(+)RORγt(+)FOXP3(+) were decreased in comparison to the EOS low asthmatics. Finally, in a group of control subjects we found that the majority of proliferating Th cells (CD4(+)CD25(+)Ki67(+)) expressed three or four transcription factors. CONCLUSIONS: The ability of human Th cells to express several regulatory transcription factors suggests that these cells may display plasticity in vivo

Scalable production of large quantities of defect-free few-layer graphene by shear exfoliation in liquids

To progress from the laboratory to commercial applications, it will be necessary to develop industrially scalable methods to produce large quantities of defect-free graphene. Here we show that high-shear mixing of graphite in suitable stabilizing liquids results in large-scale exfoliation to give dispersions of graphene nanosheets. X-ray photoelectron spectroscopy and Raman spectroscopy show the exfoliated flakes to be unoxidized and free of basal-plane defects. We have developed a simple model that shows exfoliation to occur once the local shear rate exceeds 10(4) s(-1). By fully characterizing the scaling behaviour of the graphene production rate, we show that exfoliation can be achieved in liquid volumes from hundreds of millilitres up to hundreds of litres and beyond. The graphene produced by this method performs well in applications from composites to conductive coatings. This method can be applied to exfoliate BN, MoS2 and a range of other layered crystals

Using role-play to improve students’ confidence and perceptions of communication in a simulated volcanic crisis

Traditional teaching of volcanic science typically emphasises scientific principles and tends to omit the key roles, responsibilities, protocols, and communication needs that accompany volcanic crises. This chapter provides a foundation in instructional communication, education, and risk and crisis communication research that identifies the need for authentic challenges in higher education to challenge learners and provide opportunities to practice crisis communication in real-time. We present an authentic, immersive role-play called the Volcanic Hazards Simulation that is an example of a teaching resource designed to match professional competencies. The role-play engages students in volcanic crisis concepts while simultaneously improving their confidence and perceptions of communicating science. During the role-play, students assume authentic roles and responsibilities of professionals and communicate through interdisciplinary team discussions, media releases, and press conferences. We characterised and measured the students’ confidence and perceptions of volcanic crisis communication using a mixed methods research design to determine if the role-play was effective at improving these qualities. Results showed that there was a statistically significant improvement in both communication confidence and perceptions of science communication. The exercise was most effective in transforming low-confidence and low-perception students, with some negative changes measured for our higher-learners. Additionally, students reported a comprehensive and diverse set of best practices but focussed primarily on the mechanics of science communication delivery. This curriculum is a successful example of how to improve students’ communication confidence and perceptions

Neuroadaptations in Human Chronic Alcoholics: Dysregulation of the NF-κB System

Anna Ökvist is with Karolinska Institute, Sofia Johansson is with Karolinska Institute, Alexander Kuzmin is with Karolinska Institute, Igor Bazov is with Karolinska Institute, Roxana Merino-Martinez is with Karolinska Institute, Igor Ponomarev is with UT Austin, R. Dayne Mayfield is with UT Austin, R. Adron Harris is with UT Austin, Donna Sheedy is with University of Sydney, Therese Garrick is with University of Sydney, Clive Harper is with University of Sydney, Yasmin L. Hurd is with Mount Sinai School of Medicine, Lars Terenius is with Karolinska Institute, Tomas J. Ekström is with Karolinska Institute, Georgy Bakalkin is with Karolinska Institute and Uppsala University, Tatjana Yakovleva is with Karolinska Institute and Uppsala University.Background -- Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-κB) family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics. Methods and Findings -- Analysis of DNA-binding of NF-κB (p65/p50 heterodimer) and the p50 homodimer as well as NF-κB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant κB binding factor in analyzed tissues. NF-κB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA) mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-κB target DNA sites, κB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with κB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex. Conclusions -- We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-κB, when repeated over years downregulate RELA expression and NF-κB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of κB regulated genes. Alterations in expression of p50 homodimer/NF-κB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.This work was supported by grants from the AFA Forsäkring to AK, YLH, TJE and GB, the Research Foundation of the Swedish Alcohol Retail Monopoly (SRA) and Karolinska Institutet to AK, TJE and GB, and the Swedish Science Research Council and the Swedish National Drug Policy Coordinator to GB. The Australian Brain Donor Programs NSW Tissue Resource Centre was supported by The University of Sydney, National Health and Medical Research Council of Australia, Neuroscience Institute of Schizophrenia and Allied Disorders, National Institute of Alcohol Abuse and Alcoholism and NSW Department of Health.Waggoner Center for Alcohol and Addiction Researc

Observing the temperature dependent transition of the GP2 peptide using terahertz spectroscopy

The GP2 peptide is derived from the Human Epidermal growth factor Receptor 2 (HER2/nue), a marker protein for breast cancer present in saliva. In this paper we study the temperature dependent behavior of hydrated GP2 at terahertz frequencies and find that the peptide undergoes a dynamic transition between 200 and 220 K. By fitting suitable molecular models to the frequency response we determine the molecular processes involved above and below the transition temperature (TD). In particular, we show that below TD the dynamic transition is dominated by a simple harmonic vibration with a slow and temperature dependent relaxation time constant and that above TD, the dynamic behavior is governed by two oscillators, one of which has a fast and temperature independent relaxation time constant and the other of which is a heavily damped oscillator with a slow and temperature dependent time constant. Furthermore a red shifting of the characteristic frequency of the damped oscillator was observed, confirming the presence of a non-harmonic vibration potential. Our measurements and modeling of GP2 highlight the unique capabilities of THz spectroscopy for protein characterization.Yiwen Sun, Zexuan Zhu, Siping Chen, Jega Balakrishnan, Derek Abbott, Anil T. Ahuja and Emma Pickwell-MacPherso

Lymphocyte depletion and repopulation after chemotherapy for primary breast cancer

Background: Approximately 30 % of breast cancer patients receive chemotherapy, yet little is known about influences of current regimens on circulating lymphocyte levels and phenotypes. Similarly, clinico-pathological factors that modify these influences, and implications for future immune health remain mainly unexplored. Methods: We used flow-cytometry to assess circulating lymphocyte levels and phenotypes in 88 primary breast cancer patients before chemotherapy and at time-points from 2 weeks to 9 months after chemotherapy completion. We examined circulating titres of antibodies against pneumococcal and tetanus antigens using ELISAs. Results: Levels of B, T and NK cells were significantly reduced 2 weeks after chemotherapy (p < 0.001). B cells demonstrated particularly dramatic depletion, falling to 5.4 % of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4+ T cells remained significantly depleted even 9 months post-chemotherapy (p < 0.001). Phenotypes of repopulating B and CD4+ T cells were significantly different from, and showed no sign of returning to pre-chemotherapy profiles. Repopulating B cells were highly depleted in memory cells, with proportions of memory cells falling from 38 % to 10 % (p < 0.001). Conversely, repopulating CD4+ T cells were enriched in memory cells, which increased from 63 % to 75 % (p < 0.001). Differences in chemotherapy regimen and patient smoking were associated with significant differences in depletion extent or repopulation dynamics. Titres of anti-pneumococcal and anti-tetanus antibodies were both significantly reduced post-chemotherapy and did not recover during the study (p < 0.001). Conclusion: Breast cancer chemotherapy is associated with long-term changes in immune parameters that should be considered during clinical management