A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure

The mixed problem for the Laplacian in Lipschitz domains

We consider the mixed boundary value problem or Zaremba's problem for the Laplacian in a bounded Lipschitz domain in R^n. We specify Dirichlet data on part of the boundary and Neumann data on the remainder of the boundary. We assume that the boundary between the sets where we specify Dirichlet and Neumann data is a Lipschitz surface. We require that the Neumann data is in L^p and the Dirichlet data is in the Sobolev space of functions having one derivative in L^p for some p near 1. Under these conditions, there is a unique solution to the mixed problem with the non-tangential maximal function of the gradient of the solution in L^p of the boundary. We also obtain results with data from Hardy spaces when p=1.Comment: Version 5 includes a correction to one step of the main proof. Since the paper appeared long ago, this submission includes the complete paper, followed by a short section that gives the correction to one step in the proo

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

RNAi-mediated COPS3 gene silencing inhibits metastasis of osteogenic sarcoma cells

Metastatic disease is the primary cause of mortality among patients with osteogenic sarcoma (OGS). In this study, we aimed to identify the relationship of COPS3 gene expression to metastasis. Immunohistochemical staining for COPS3 was performed on 65 OGS samples (37 without and 28 with metastatic disease); 18.9% (7/37) of specimens from patients with no metastasis and 57.1% (16/28) of specimens from patients with metastasis showed intense staining of COPS3. Comparison of COPS3 expression between a poorly metastatic osteosarcoma cell line (SAOS-2) and highly metastatic osteosarcoma cell line (HOS) showed stronger expression of COPS3 in HOS cells. Inhibiting COPS3 function by siRNA resulted in reduced proliferation and migration of HOS cells. Inhibition of COPS3 gene downregulated expression of the MAPK signaling pathway, which has an important role in metastasis of OGS. Our results suggested that overexpression of the COPS3 gene might have important roles in metastasis of osteosarcoma cells

Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers

<p>Abstract</p> <p>Background</p> <p>Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers.</p> <p>Methods</p> <p>Caucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio ≥ 70% and ppFEV₁≥ 80% (n = 311) despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders.</p> <p>Results</p> <p>Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile → Val: p < 0.003; S2, Gly → Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25–75 (p values 0.001 – 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities.</p> <p>Conclusion</p> <p>Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.</p

Nash Social Welfare in Selfish and Online Load Balancing

In load balancing problems there is a set of clients, each wishing to select a resource from a set of permissible ones, in order to execute a certain task. Each resource has a latency function, which depends on its workload, and a client's cost is the completion time of her chosen resource. Two fundamental variants of load balancing problems are {\em selfish load balancing} (aka. {\em load balancing games}), where clients are non-cooperative selfish players aimed at minimizing their own cost solely, and {\em online load balancing}, where clients appear online and have to be irrevocably assigned to a resource without any knowledge about future requests. We revisit both selfish and online load balancing under the objective of minimizing the {\em Nash Social Welfare}, i.e., the geometric mean of the clients' costs. To the best of our knowledge, despite being a celebrated welfare estimator in many social contexts, the Nash Social Welfare has not been considered so far as a benchmarking quality measure in load balancing problems. We provide tight bounds on the price of anarchy of pure Nash equilibria and on the competitive ratio of the greedy algorithm under very general latency functions, including polynomial ones. For this particular class, we also prove that the greedy strategy is optimal as it matches the performance of any possible online algorithm

Induction of apoptosis in myeloid leukaemic cells by ribozymes targeted against AML1/MTG8

The translocation (8;21)(q22;q22) is a karyotypic abnormality detected in acute myeloid leukaemia (AML) M2 and results in the formation of the chimeric fusion gene AML1/MTG8. We previously reported that two hammerhead ribozymes against AML1/MTG8 cleave this fusion transcript and also inhibit the proliferation of myeloid leukaemia cell line Kasumi-1 which possesses t(8;21)(q22;q22). In this study, we investigated the mechanisms of inhibition of proliferation in myeloid leukaemic cells with t(8;21)(q22;q22) by ribozymes. These ribozymes specifically inhibited the growth of Kasumi-1 cells, but did not affect the leukaemic cells without t(8;21)(q22;q22). We observed the morphological changes including chromatin condensation, fragmentation and the formation of apoptotic bodies in Kasumi-1 cells incubated with ribozymes for 7 days. In addition, DNA ladder formation was also detected after incubation with ribozymes which suggested the induction of apoptosis in Kasumi-1 cells by the AML1/MTG8 ribozymes. However, the ribozymes did not induce the expression of CD11b and CD14 antigens in Kasumi-1 cells. The above data suggest that these ribozymes therefore inhibit the growth of myeloid leukaemic cells with t(8;21)(q22;q22) by the induction of apoptosis, but not differentiation. We conclude therefore that the ribozymes targeted against AML1/MTG8 may have therapeutic potential for patients with AML carrying t(8;21)(q22;q22) while, in addition, the product of the chimeric gene is responsible for the pathogenesis of myeloid leukaemia. © 1999 Cancer Research Campaig

Intrinsic Order and Disorder in the Bcl-2 Member Harakiri: Insights into Its Proapoptotic Activity

Harakiri is a BH3-only member of the Bcl-2 family that localizes in membranes and induces cell death by binding to prosurvival Bcl-xL and Bcl-2. The cytosolic domain of Harakiri is largely disorder with residual α-helical conformation according to previous structural studies. As these helical structures could play an important role in Harakiri's function, we have used NMR and circular dichroism to fully characterize them at the residue-atomic level. In addition, we report structural studies on a peptide fragment spanning Harakiri's C-terminal hydrophobic sequence, which potentially operates as a transmembrane domain. We initially checked by enzyme immunoassays and NMR that peptides encompassing different lengths of the cytosolic domain are functional as they bind Bcl-xL and Bcl-2. The structural data in water indicate that the α-helical conformation is restricted to a 25-residue segment comprising the BH3 domain. However, structure calculation was precluded because of insufficient NMR restraints. To bypass this problem we used alcohol-water mixture to increase structure population and confirmed by NMR that the conformation in both milieus is equivalent. The resulting three-dimensional structure closely resembles that of peptides encompassing the BH3 domain of BH3-only members in complex with their prosurvival partners, suggesting that preformed structural elements in the disordered protein are central to binding. In contrast, the transmembrane domain forms in micelles a monomeric α-helix with a population close to 100%. Its three-dimensional structure here reported reveals features that explain its function as membrane anchor. Altogether these results are used to propose a tentative structural model of how Harakiri works

Detection of Mycobacterium ulcerans by the Loop Mediated Isothermal Amplification Method

In order to develop a simple and rapid test that can be used to diagnose Buruli ulcer under field conditions, we modified the conventional LAMP assay by using a disposable pocket warmer as a heating device for generating a constant temperature for the test reaction and employed the use of crude sample preparations consisting of boiled and unboiled extracts of the clinical specimen instead of using purified DNA as the diagnostic specimen. Thirty clinical specimens from suspected Buruli ulcer patients were investigated by the modified LAMP (or pocket warmer LAMP) and the conventional LAMP, as well as IS2404 PCR, a reference method for the detection of Mycobacterium ulcerans. There was no significant difference in the detection rate (63–70%) in all of the methods when purified samples were used for the tests. On the other hand the use of crude specimen preparation resulted in a drop in detection rate (30–40%). This study demonstrates that the LAMP test can be used for rapid detection of M. ulcerans when purified DNA preparations are used. With further improvements in the sample reaction, as well as in specimen purification, the pocket warmer LAMP may provide a simple and rapid diagnostic test for Buruli ulcer

The benefits of participatory methodologies to develop effective community dialogue in the context of a microbicide trial feasibility study in Mwanza, Tanzania

BACKGROUND: As part of a microbicide trial feasibility study among women at high-risk of HIV and sexually transmitted infections in Mwanza City, northern Tanzania we used participatory research tools to facilitate open dialogue and partnership between researchers and study participants. METHODS: A mobile community-based sexual & reproductive health service was established in ten city wards. Wards were divided into seventy-eight geographical clusters and representatives at cluster and ward level elected in a process facilitated by the projects Community Liaison Officer. A city-level Community Advisory Committee (CAC) with representatives from each ward was established. Workshops and community meetings at ward and city-level were conducted to explore project-related concerns using tools adapted from participatory learning and action techniques such as listing, scoring, ranking, chapatti diagrams and pair-wise matrices. RESULTS: Key issues identified included beliefs that blood specimens were being sold for witchcraft purposes; worries about specula not being clean; inadequacy of transport allowances; and delays in reporting laboratory test results to participants. To date, the project has responded by inviting members of the CAC to visit the laboratory to observe how blood and genital specimens are prepared; demonstrated the use of the autoclave to community representatives; raised reimbursement levels; introduced HIV rapid testing in the clinic; and streamlined laboratory reporting procedures. CONCLUSIONS: Participatory techniques were instrumental in promoting meaningful dialogue between the research team, study participants and community representatives in Mwanza, allowing researchers and community representatives to gain a shared understanding of project-related priority areas for intervention