PDB-Explorer: a web-based interactive map of the protein data bank in shape space

Background The RCSB Protein Data Bank (PDB) provides public access to experimentally determined 3D-structures of biological macromolecules (proteins, peptides and nucleic acids). While various tools are available to explore the PDB, options to access the global structural diversity of the entire PDB and to perceive relationships between PDB structures remain very limited. Methods A 136-dimensional atom pair 3D-fingerprint for proteins (3DP) counting categorized atom pairs at increasing through-space distances was designed to represent the molecular shape of PDB-entries. Nearest neighbor searches examples were reported exemplifying the ability of 3DP-similarity to identify closely related biomolecules from small peptides to enzyme and large multiprotein complexes such as virus particles. The principle component analysis was used to obtain the visualization of PDB in 3DP-space. Results The 3DP property space groups proteins and protein assemblies according to their 3D-shape similarity, yet shows exquisite ability to distinguish between closely related structures. An interactive website called PDB-Explorer is presented featuring a color-coded interactive map of PDB in 3DP-space. Each pixel of the map contains one or more PDB-entries which are directly visualized as ribbon diagrams when the pixel is selected. The PDB-Explorer website allows performing 3DP-nearest neighbor searches of any PDB-entry or of any structure uploaded as protein-type PDB file. All functionalities on the website are implemented in JavaScript in a platform-independent manner and draw data from a server that is updated daily with the latest PDB additions, ensuring complete and up-to-date coverage. The essentially instantaneous 3DP-similarity search with the PDB-Explorer provides results comparable to those of much slower 3D-alignment algorithms, and automatically clusters proteins from the same superfamilies in tight groups. Conclusion A chemical space classification of PDB based on molecular shape was obtained using a new atom-pair 3D-fingerprint for proteins and implemented in a web-based database exploration tool comprising an interactive color-coded map of the PDB chemical space and a nearest neighbor search tool. The PDB-Explorer website is freely available at www.​cheminfo.​org/​pdbexplorer and represents an unprecedented opportunity to interactively visualize and explore the structural diversity of the PDB.

The bona fide mouse U7 snRNA gene maps to a different chromosome than two U7 pseudogenes.

The U7 snRNA, together with both common and unique snRNP proteins, forms the U7 snRNP particle. This particle is a major component of the 3' processing machinery that converts histone pre-mRNA into mature mRNA in the eukaryotic nucleus. The genes for many snRNAs are present in multiple copies and often have many pseudogenes. Southern blot experiments using U7 oligonucleotide and gene probes have identified only one strongly hybridizing band and three weakly hybridizing bands in mouse genomic DNA. Previously, two laboratories isolated genomic clones encoding one functional U7 gene and three presumed pseudogenes. Since all the genes were isolated on separate, nonoverlapping genomic fragments, the four genes are not tightly clustered in the mouse genome. In this study, we use fluorescence in situ hybridization to determine the chromosomal locations of these clones and their possible linkage to histone loci. Two of the pseudogenes map to mouse Chromosome 1, but are many megabases apart, whereas the active U7 gene maps to Chromosome 6. Possible mechanisms for this localization pattern are discussed.

Incidence of AIDS-Defining and Other Cancers in HIV-Positive Children in South Africa: Record Linkage Study.

BACKGROUND Little is known on the risk of cancer in HIV-positive children in sub-Saharan Africa. We examined incidence and risk factors of AIDS-defining and other cancers in pediatric antiretroviral therapy (ART) programs in South Africa. METHODS We linked the records of five ART programs in Johannesburg and Cape Town to those of pediatric oncology units, based on name and surname, date of birth, folder and civil identification numbers. We calculated incidence rates and obtained hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression models including ART, sex, age, and degree of immunodeficiency. Missing CD4 counts and CD4% were multiply imputed. Immunodeficiency was defined according to World Health Organization 2005 criteria. RESULTS Data of 11,707 HIV-positive children were included in the analysis. During 29,348 person-years of follow-up 24 cancers were diagnosed, for an incidence rate of 82 per 100,000 person-years (95% CI 55-122). The most frequent cancers were Kaposi Sarcoma (34 per 100,000 person-years) and Non Hodgkin Lymphoma (31 per 100,000 person-years). The incidence of non AIDS-defining malignancies was 17 per 100,000. The risk of developing cancer was lower on ART (HR 0.29, 95%CI 0.09-0.86), and increased with age at enrolment (>10 versus <3 years: HR 7.3, 95% CI 2.2-24.6) and immunodeficiency at enrolment (advanced/severe versus no/mild: HR 3.5, 95%CI 1.1-12.0). The HR for the effect of ART from complete case analysis was similar but ceased to be statistically significant (p=0.078). CONCLUSIONS Early HIV diagnosis and linkage to care, with start of ART before advanced immunodeficiency develops, may substantially reduce the burden of cancer in HIV-positive children in South Africa and elsewhere.

Record linkage to correct under-ascertainment of cancers in HIV cohorts: the Sinikithemba HIV clinic linkage project.

The surveillance of HIV-related cancers in South Africa is hampered by the lack of systematic collection of cancer diagnoses in HIV cohorts and the absence of HIV status in cancer registries. To improve cancer ascertainment and estimate cancer incidence, we linked records of adults (aged ≥ 16 years) on antiretroviral treatment (ART) enrolled at Sinikithemba HIV clinic, McCord Hospital in KwaZulu-Natal (KZN) with the cancer records of public laboratories in KZN province using probabilistic record linkage methods. We calculated incidence rates for all cancers, Kaposi sarcoma (KS), cervix, non-Hodgkin's lymphoma and non-AIDS defining cancers (NADCs) before and after inclusion of linkage-identified cancers with 95% confidence intervals (CI). A total of 8,721 records of HIV-positive patients were linked with 35,536 cancer records. Between 2004 and 2010 we identified 448 cancers, 82% (n=367) were recorded in the cancer registry only, 10% (n=43) in the HIV cohort only and 8% (n=38) both in the HIV cohort and the cancer registry. The overall cancer incidence rate in patients starting ART increased from 134 (95% CI 91-212) to 877 (95% CI 744-1,041) after inclusion of linkage-identified cancers. Incidence rates were highest for KS (432, 95% CI 341-555), followed by cervix (259, 95% CI 179-390) and NADCs (294, 95% CI 223-395) per 100,000 person-years. Ascertainment of cancer in HIV cohorts is incomplete, probabilistic record linkage is both feasible and essential for cancer ascertainment. This article is protected by copyright. All rights reserved.

Traditional linkage analysis in admixed families

Currently there is no general method to study the impact of population admixture within families on the assumptions of random mating and consequently, Hardy-Weinberg equilibrium (HWE) and linkage equilibrium (LE) and on the inference obtained from traditional linkage analysis. ^ First, through simulation, the effect of admixture of two populations on the log of the odds (LOD) score was assessed, using Prostate Cancer as the typical disease model. Comparisons between simulated mixed and homogeneous families were performed. LOD scores under both models of admixture (within families and within a data set of homogeneous families) were closest to the homogeneous family scores of the population having the highest mixing proportion. Random sampling of families or ascertainment of families with disease affection status did not affect this observation, nor did the mode of inheritance (dominant/recessive) or sample size. ^ Second, after establishing the effect of admixture on the LOD score and inference for linkage, the presence of induced disequilibria by population admixture within families was studied and an adjustment procedure was developed. The adjustment did not force all disequilibria to disappear but because the families were adjusted for the population admixture, those replicates where the disequilibria exist are no longer affected by the disequilibria in terms of maximization for linkage. Furthermore, the adjustment was able to exclude uninformative families or families that had such a high departure from HWE and/or LE that their LOD scores were not reliable. ^ Together these observations imply that the presence of families of mixed population ancestry impacts linkage analysis in terms of the LOD score and the estimate of the recombination fraction. ^

Positional candidate cloning of the RP10 form of retinitis pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerations that affects over one million people worldwide. To date, 11 autosomal dominant, 13 autosomal recessive, and 5 X-linked forms of retinitis pigmentosa have been identified through linkage analysis, but the disease-causing genes and mutations have been found for only half of these loci. My research uses a positional candidate cloning approach to identify the gene and mutations responsible for one type of autosomal dominant retinitis pigmentosa, RP10. The premise is that identifying the genes and mutations responsible for disease will provide insight into disease mechanisms and provide treatment options. Previous research mapped the RP10 locus to a 5cM region on chromosome 7q31 between markers D7S686 and D7S530. Linkage and fine-point haplotype analysis was used to reduce and refine the RP10 disease interval to a 4cM region located between D7S2471 and a new marker located 45,000bp telomeric of D7S461. In order to identify genes located in the RP10 interval, an extensive EST map was created of this region. Five EST clusters from this map were analyzed to determine if mutations in these genes cause the RP10 form of retinitis pigmentosa. The genomic structure of a known metabotrophic glutamate receptor, GRMS8, was determined first. DNA sequencing of GRM8 in RP10 family members did not identify any disease-causing mutations. Four other EST clusters (A170, A173, A189, and A258) were characterized and determined to be part of the same gene, UBNL1 (ubinuclein-like 1). The full-length mRNA sequence and genomic structure of UBNL1 was determined and then screened in patients. No disease-causing mutations were identified in any of the RP10 family members tested. Recent data made available with the release of the public and Celera genome assemblies indicates that UBNL1 is outside of the RP10 disease region. Despite this complication, characterization of UBNL1 is still important in the understanding of normal visual processes and it is possible that mutations in UBNL1 could cause other forms of retinopathy. The EST map and list of RP10 candidates will continue to aid others in the search for the RP10 gene and mutations. ^

The identification and characterization of the Staphylococcus aureus microbial immunomodulatory molecules (MIMS) Map and Efb

Staphylococcus aureus is an opportunistic pathogen that is a major health threat in the clinical and community settings. An interesting hallmark of patients infected with S. aureus is that they do not usually develop a protective immune response and are susceptible to reinfection, in part because of the ability of S. aureus to modulate host immunity. The ability to evade host immune responses is a key contributor to the infection process and is critical in S. aureus survival and pathogenesis. This study investigates the immunomodulatory effects of two secreted proteins produced by S. aureus, the MHC class II analog protein (Map) and the extracellular fibrinogen-binding protein (Efb). Map has been demonstrated to modulate host immunity by interfering with T cell function. Map has been shown to significantly reduce T cell proliferative responses and significantly reduce delayed-type hypersensitivity responses to challenge antigen. In addition, the effects of Map on the infection process were tested in a mouse model of infection. Mice infected with Map− S. aureus (Map deficient strain) presented with significantly reduced levels of arthritis, osteomyelitis and abscess formation compared to mice infected with the wild-type Map+S. aureus strain suggesting that Map−S. aureus is much less virulent than Map+S. aureus. Furthermore, Map−S. aureus-infected nude mice developed arthritis and osteomyelitis to a severity similar to Map +S. aureus-infected controls, suggesting that T cells can affect disease outcome following S. aureus infection and Map may attenuate cellular immunity against S. aureus. The extracellular fibrinogen-binding protein (Efb) was identified when cultured S. aureus supernatants were probed with the complement component C3. The binding of C3 to Efb resulted in studies investigating the effects of Efb on complement activation. We have demonstrated that Efb can inhibit both the classical and alternative complement pathways. Moreover, we have shown that Efb can inhibit complement mediated opsonophagocytosis. Further studies have characterized the Efb-C3 binding interaction and localized the C3-binding domain to the C-terminal region of Efb. In addition, we demonstrate that Efb binds specifically to a region within the C3d fragment of C3. This study demonstrates that Map and Efb can interfere with both the acquired and innate host immune pathways and that these proteins contribute to the success of S. aureus in evading host immunity and in establishing disease. ^

Candidate gene identification following linkage: Search for hypertension susceptibility genes

Following up genetic linkage studies to identify the underlying susceptibility gene(s) for complex disease traits is an arduous yet biologically and clinically important task. Complex traits, such as hypertension, are considered polygenic with many genes influencing risk, each with small effects. Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contribute to blood pressure levels and hypertension status. Using combined positional candidate gene methods, the Family Blood Pressure Program has concentrated efforts in investigating this region of chromosome 2 in an effort to identify underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in eight positional candidate genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. To adjust for multiple comparisons, resampling-based false discovery adjustment was applied, extending traditional resampling methods to sibship samples. Following this adjustment for multiple comparisons, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two populations of African Americans (N = 461; N = 778) and two of whites (N = 550; N = 967). Again, SNPs within SLC4A5 were significantly associated with blood pressure levels and hypertension status. While not identifying a single causal DNA sequence variation that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene, validating previous evidence for one or more genes on chromosome 2 that influence hypertension related phenotypes in the population-at-large. The methodology and results reported provide a case study of one approach for following up the results of genetic linkage analyses to identify genes influencing complex traits. ^

Building a Globally Distributed Historical Sheet Map Set

This paper describes the procedures used to create a distributed collection of topographic maps of the Austro-Hungarian Empire, the Spezialkarte der Öesterriechisch-ungarnischen Monarchie, Masse. 1:75,000 der natur. This set of maps was published in Vienna over a period of years from 1877 to 1914. The part of the set used in this project includes 776 sheets; all sheets from all editions number over 3,665. The paper contains detailed information on how the maps were converted to digital images, how metadata were prepared, and how Web-browser access was created using ArcIMS Metadata Server. The project, funded by a 2004 National Leadership Grant from the Institute for Museums and Library Science (IMLS), was a joint project of the Homer Babbidge Library Map and Geographic Information Center at the University of Connecticut, the New York Public Library, and the American Geographical Society’s Map Library at the University of Wisconsin Milwaukee.

Caenorhabditis elegans germinal center kinase (Gck-1) is a p-body component that inhibits precocious ectopic MAP kinase dependent meiotic maturation

The Caenorhabditis elegans germline is an excellent model system for studying meiosis, as the gonad contains germ cells in all stages of meiosis I prophase in a linear temporal and spatial pattern. To form healthy gametes, many events must be coordinated. Failure of any step in the process can reduce fertility. Here, we describe a C. elegans Germinal Center Kinase, GCK-1, that is essential for the accurate progression of germ cells through meiosis I prophase. In the absence of GCK-1, germ cells undergo precocious maturation due to the activation of a specific MAP kinase isoform. Furthermore, GCK-1 localizes to P-bodies, RNP particles that have been implicated in RNA degradation and translational control. Like two other components of C. elegans germline P-bodies, GCK-1 functions to limit physiological germ cell apoptosis. This is the first study to identify a role for a GCK-III kinase in metazoan germ cell development and to link P-body function with MAP kinase activation and germ cell maturation. ^

Identification of genetic variation influencing apolipoprotein E levels: Follow-up of genome-wide linkage scans in the GENOA study

Apolipoprotein E (ApoE) plays a major role in the metabolism of high density and low density lipoproteins (HDL and LDL). Its common protein isoforms (E2, E3, E4) are risk factors for coronary artery disease (CAD) and explain between 16 to 23% of the inter-individual variation in plasma apoE levels. Linkage analysis has been completed for plasma apoE levels in the GENOA study (Genetic Epidemiology Network of Atherosclerosis). After stratification of the population by lipoprotein levels and body mass index (BMI) to create more homogeneity with regard to biological context for apoE levels, Hispanic families showed significant linkage on chromosome 17q for two strata (LOD=2.93 at 104 cM for a low cholesterol group, LOD=3.04 at 111 cM for a low cholesterol, high HDLC group). Replication of 17q linkage was observed for apoB and apoE levels in the unstratified Hispanic and African-American populations, and for apoE levels in African-American families. Replication of this 17q linkage in different populations and strata provides strong support for the presence of gene(s) in this region with significant roles in the determination of inter-individual variation in plasma apoE levels. Through a positional and functional candidate gene approach, ten genes were identified in the 17q linked region, and 62 polymorphisms in these genes were genotyped in the GENOA families. Association analysis was performed with FBAT, GEE, and variance-component based tests followed by conditional linkage analysis. Association studies with partial coverage of TagSNPs in the gene coding for apolipoprotein H (APOH) were performed, and significant results were found for 2 SNPs (APOH_20951 and APOH_05407) in the Hispanic low cholesterol strata accounting for 3.49% of the inter-individual variation in plasma apoE levels. Among the other candidate genes, we identified a haplotype block in the ACE1 gene that contains two major haplotypes associated with apoE levels as well as total cholesterol, apoB and LDLC levels in the unstratified Hispanic population. Identifying genes responsible for the remaining 60% of inter-individual variation in plasma apoE level, will yield new insights into the understanding of genetic interactions involved in the lipid metabolism, and a more precise understanding of the risk factors leading to CAD. ^

THE LOGIC OF NOMINAL RECORD LINKAGE WITH A CASE STUDY FROM LAREDO, TEXAS

The Laredo Epidemiology Project is a study of the patterns of degenerative disease, particularly cancer, in the families of Laredo, Texas. The genealogical history of Laredo was reconstructed by the grouping of 350,000 individual church and civil vital event records into multi-generational families, with record linkage based on matching names. Mortality data from death records are mapped onto these pedigrees for analysis. This dissertation describes the construction of the data base and the logic upon which decisions were based. ^

Alpine permafrost index map

The objective of this study is the production of an Alpine Permafrost Index Map (APIM) covering the entire European Alps. A unified statistical model that is based on Alpine-wide permafrost observations is used for debris and bedrock surfaces across the entire Alps. The explanatory variables of the model are mean annual air temperatures, potential incoming solar radiation and precipitation. Offset terms were applied to make model predictions for topographic and geomorphic conditions that differ from the terrain features used for model fitting. These offsets are based on literature review and involve some degree of subjective choice during model building. The assessment of the APIM is challenging because limited independent test data are available for comparison and these observations represent point information in a spatially highly variable topography. The APIM provides an index that describes the spatial distribution of permafrost and comes together with an interpretation key that helps to assess map uncertainties and to relate map contents to their actual expression in terrain. The map can be used as a first resource to estimate permafrost conditions at any given location in the European Alps in a variety of contexts such as research and spatial planning. Results show that Switzerland likely is the country with the largest permafrost area in the Alps, followed by Italy, Austria, France and Germany. Slovenia and Liechtenstein may have marginal permafrost areas. In all countries the permafrost area is expected to be larger than the glacier-covered area.