Regions Of Potential Interest Research Articles

Abstract PO-202: Copy number variation (CNV) analysis identifies variants in 1p36 in African American and Caucasian hereditary prostate cancer cases

Abstract Prostate cancer (PCa) is a common malignancy which affects 1 in 8 men. There is a significant racial disparity and African American (AA) males are more at risk for developing such cancers, at a rate of almost double compared to the males of European ancestry (EA). So far, not much is known about the role of germline copy number variations (CNVs) in this health disparity. Our previous work has shown several genetic regions with CNVs in both AA and EA hereditary prostate cancer (HPC) cases. The goal of this project was to detect germline CNVs in the targeted resequencing data spanning 9 Mb region in 1p36, that was previously identified by microarray and whole exome sequencing analyses. For this study, a total of 50 individuals were used, 25 AA and 25 EA men from HPC families. We have used three CNV calling algorithms: XHMM, CANOES, and GATK4. First, we focused on four PCa associated genes: NBPF1, NBL1, SRSF10, and RHD, that were previously identified in our study. In the current CNV analysis, XHMM identified deletions in NBPF1 in several samples in both AA and EA cases. GATK4 was unable to call any CNVs in this gene. NBL1 had no identified deletions in any tool, despite previous microarray data to the contrary. XHMM identified full deletions of SRSF10 in most of the cases, while GATK4 identified partial deletion in several cases from both ancestries, but more frequently in AA cases. Finally, a deletion was detected in RHD in only a few cases, and the deletion was confirmed by both XHMM and GATK4 algorithms. Deletion in RHD was more common in the EA population than the AA population. CANOES was unable to identify any variants within our regions of interest. We then expanded our search to other identified variants to identify regions commonly detected by the CNV calling algorithms. A region of deletion was detected in the CELA3A gene (reported to be downregulated in pancreatic and prostate cancer) and a region between AKR7L and AKR7A3 both of which are found to be frequently mutated in cancer cells. XHMM called the deletion of both of these regions at a much higher rate than GATK4: nearly in all our cases from the two ancestries, compared to only a few in GATK4 and CANOES. The few PCa cases who had deletions across all tools were always in the AA population. Altogether, this new analytical strategy establishes the usefulness of applying multiple CNV callers in identifying regions of potential interest, as well as verifying the results from previous studies of PCa. Results from this study may hold valuable information in finding potential biomarkers to address PCa health disparity in the future. Further validation of the identified variants is ongoing. Citation Format: Alan F. Williams, Kirsten W. Termine, John Waldron, Oliver Sartor, Joan Bailey-Wilson, Diptasri Mandal. Copy number variation (CNV) analysis identifies variants in 1p36 in African American and Caucasian hereditary prostate cancer cases [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-202.

Human- and lightning-caused wildland fire ignition clusters in British Columbia, Canada

Wildland fire is a common occurrence in western Canada, with record-setting area burned recorded in British Columbia (BC) in the past decade. Here, we used the unsupervised machine learning algorithm HDBSCAN to identify high-density clusters of both human- and lightning-caused wildfire ignitions in BC using data from 2006 to 2020. We found that human-caused ignition clusters tended to occur around population centres, First Nations communities, roads and valleys, and were more common in the southern half of the province, which is more populated. Lightning-ignition clusters were generally fewer in number and larger in size than human-caused fires for most hyperparameter settings. There were significant differences (X2 = 1884.8, d.f. = 7, P-value <2.2 × 10−16) in fuels associated with lightning- versus human-caused ignition clusters, with human-ignition cluster fires being more often found within leafless aspen (D1) and ponderosas pine and Douglas fir (C7) fuel types. These high-density clusters highlight regions where the greatest densities of both lightning- and human-caused fires have occurred in the province, thereby identifying regions of potential interest to wildland fire managers, researchers and various communities and industries.

From discrete element simulation data to process insights

Industrial-scale discrete element simulations typically generate Gigabytes of data per time step, which implies that even opening a single file may require 5 - 15 minutes on conventional magnetic storage devices. Data science’s inherent multi-disciplinary nature makes the extraction of useful information challenging, often leading to undiscovered details or new insights. This study explores the potential of statistical learning to identify potential regions of interest for large scale discrete element simulations. We demonstrate that our in-house knowledge discovery and data mining system (KDS) can decompose large datasets into i) regions of potential interest to the analyst, ii) multiple decompositions that highlight different aspects of the data, iii) simplify interpretation of DEM generated data by focusing attention on the interpretation of automatically decomposed regions, and iv) streamline the analysis of raw DEM data by letting the analyst control the number of decomposition and the way the decompositions are performed. Multiple decompositions can be automated in parallel and compressed, enabling agile engagement with the analyst’s processed data. This study focuses on spatial and not temporal inferences.

Genetic correlates of therapeutic toxicities of stage III colon carcinoma patients treated with adjuvant FOLFOX+/-cetuximab (NCCTG N0147, Alliance).

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P < 5x10-8was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10−10 and OR = 1.5, P = 2.7×10−10, respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly & Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .

Role of Lipids in the Reaction Coordinate of GlpG Rhomboid Protease

Rhomboid proteases function in hydrated lipid membrane environments that can impact significantly the catalytic activity of the enzyme. How lipids participate in the reaction coordinate of rhomboid proteases is, however, unclear. We address this question by performing all-atom molecular dynamics simulations of the rhomboid protease from Escherichia coli, GlpG. We study GlpG starting from three different protein crystal structures, and explore interactions with lipids by considering five one-component lipid membranes with different lipid headgroups or alkyl chains, and in mixed membranes of phosphatidylethanolamine and phosphatidylgylcerol lipids. Lipid alkyl chains can visit inter-helical regions of the protein close to the gate helix, which can indicate regions of potential interest for substrate binding. Variability in how the protein can interact with lipids closest to the helical gate region suggests that membrane environments may impact proteolysis by participating in the substrate-binding step of the reaction coordinate.Research was supported in part by funding from the Excellence Initiative of the German Federal and State Governments via the Freie Universitat Berlin, and by an allocation of computing time from HLRN, The North-German Supercomputing Center (bec00076).

Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.

On Pixel-Wise Explanations for Non-Linear Classifier Decisions by Layer-Wise Relevance Propagation.

Understanding and interpreting classification decisions of automated image classification systems is of high value in many applications, as it allows to verify the reasoning of the system and provides additional information to the human expert. Although machine learning methods are solving very successfully a plethora of tasks, they have in most cases the disadvantage of acting as a black box, not providing any information about what made them arrive at a particular decision. This work proposes a general solution to the problem of understanding classification decisions by pixel-wise decomposition of nonlinear classifiers. We introduce a methodology that allows to visualize the contributions of single pixels to predictions for kernel-based classifiers over Bag of Words features and for multilayered neural networks. These pixel contributions can be visualized as heatmaps and are provided to a human expert who can intuitively not only verify the validity of the classification decision, but also focus further analysis on regions of potential interest. We evaluate our method for classifiers trained on PASCAL VOC 2009 images, synthetic image data containing geometric shapes, the MNIST handwritten digits data set and for the pre-trained ImageNet model available as part of the Caffe open source package.

Discovery of Path Nearby Clusters in Spatial Networks

The discovery of regions of interest in large cities is an important challenge. We propose and investigate a novel query called the path nearby cluster (PNC) query that finds regions of potential interest (e.g., sightseeing places and commercial districts) with respect to a user-specified travel route. Given a set of spatial objects $O$ (e.g., POIs, geo-tagged photos, or geo-tagged tweets) and a query route $q$ , if a cluster $c$ has high spatial-object density and is spatially close to $q$ , it is returned by the query (a cluster is a circular region defined by a center and a radius). This query aims to bring important benefits to users in popular applications such as trip planning and location recommendation. Efficient computation of the PNC query faces two challenges: how to prune the search space during query processing, and how to identify clusters with high density effectively. To address these challenges, a novel collective search algorithm is developed. Conceptually, the search process is conducted in the spatial and density domains concurrently. In the spatial domain, network expansion is adopted, and a set of vertices are selected from the query route as expansion centers. In the density domain, clusters are sorted according to their density distributions and they are scanned from the maximum to the minimum. A pair of upper and lower bounds are defined to prune the search space in the two domains globally. The performance of the PNC query is studied in extensive experiments based on real and synthetic spatial data.

User‐driven Feature Space Transformation

AbstractInteractive visualization systems for exploring and manipulating high‐dimensional feature spaces have experienced a substantial progress in the last few years. State‐of‐art methods rely on solid mathematical and computational foundations that enable sophisticated and flexible interactive tools. Current methods are even capable of modifying data attributes during interaction, highlighting regions of potential interest in the feature space, and building visualizations that bring out the relevance of attributes. However, those methodologies rely on complex and non‐intuitive interfaces that hamper the free handling of the feature spaces. Moreover, visualizing how neighborhood structures are affected during the space manipulation is also an issue for existing methods. This paper presents a novel visualization‐assisted methodology for interacting and transforming data attributes embedded in feature spaces. The proposed approach relies on a combination of multidimensional projections and local transformations to provide an interactive mechanism for modifying attributes. Besides enabling a simple and intuitive visual layout, our approach allows the user to easily observe the changes in neighborhood structures during interaction. The usefulness of our methodology is shown in an application geared to image retrieval.

Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics

Age-related macular degeneration (AMD) is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs), and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3) and glutathione S transferase genes (GSTM1 and GSTT1) have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD.

Saliency-Assisted Navigation of Very Large Landscape Images

The field of visualization has addressed navigation of very large datasets, usually meshes and volumes. Significantly less attention has been devoted to the issues surrounding navigation of very large images. In the last few years the explosive growth in the resolution of camera sensors and robotic image acquisition techniques has widened the gap between the display and image resolutions to three orders of magnitude or more. This paper presents the first steps towards navigation of very large images, particularly landscape images, from an interactive visualization perspective. The grand challenge in navigation of very large images is identifying regions of potential interest. In this paper we outline a three-step approach. In the first step we use multi-scale saliency to narrow down the potential areas of interest. In the second step we outline a method based on statistical signatures to further cull out regions of high conformity. In the final step we allow a user to interactively identify the exceptional regions of high interest that merit further attention. We show that our approach of progressive elicitation is fast and allows rapid identification of regions of interest. Unlike previous work in this area, our approach is scalable and computationally reasonable on very large images. We validate the results of our approach by comparing them to user-tagged regions of interest on several very large landscape images from the Internet.

Are CML Lymphoid Blast Crisis and Ph Positive ALL Genomically Indistinguishable?

AbstractAbstract 4464Philadelphia positive malignant disorders are a clinically divergent group of hemoblastoses with a unique identifying feature, the BCR/ABL1 fusion gene, usually resulting from the chromosome rearrangement t(9;22)(q34;q11) or its variants, that leads to constitutive expression of an aberrant tyrosine kinase. These include chronic myeloid leukaemia (CML) and de novo acute leukaemia of both myeloid Ph(+)AML and lymphoid origin Ph(+)ALL. The latter two disorders are clinically aggressive and therapy challenging even in the era of the powerful tyrosine kinase inhibitors. CML is a multistage progressive disease, which if untreated, inevitably ends as fatal acute leukaemia, either myeloid or lymphoid. The latter is often thought to be indistinguishable from Ph(+)ALL, the most common type of ALL in adults. We have identified DNA sequences the imbalances of which appear to be significantly associated with the disease stage and lineage origin in CML and Ph(+)ALL samples. We used array CGH at a resolution of ~2kb to explore hot spot regions obtained from 102 patient samples comprising 92 CML and controls together with 10 Ph(+)ALL and show how Significance Analysis of Microarrays (1) can be used to identify differences in the genome profile of de novo Ph(+)ALL and lymphoid blast transformation of CML. We show that lymphoid blast crisis CML differs significantly from Ph(+)ALL not only due to the presence of 9p deletions but also due to genomic gains in other chromosomes. Furthermore we identify a sub group of Ph(+)ALL with a distinctive genomic profile. Having identified genome regions of potential interest, ranked in order of significance, out of the 100's of thousands of array results, it is then a challenge to design further experiments to evaluate their contribution to the biology of the BCR/ABL positive disease.1 Tusher V, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98:5116-5121 (2001). Disclosures:No relevant conflicts of interest to declare.

Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Ecogeographic and evolutionary approaches to improving adaptation of autumn-sown chickpea ( Cicer arietinum L.) to terminal drought: The search for reproductive chilling tolerance

Terminal drought is the most important abiotic stress of dryland chickpea. The principal adaptive strategy of the crop is drought escape through early phenology. In regions where average temperatures at flowering <14–16 °C, such as southern Australia or northern South Asia, the lack of reproductive chilling tolerance forces chickpea to delay podset. This delay compromises drought escape by exposing chickpea to terminal drought during much of the pod filling phase, reducing yield potential and stability, depending on seasonal climatic fluctuations. This paper defines chickpea growing seasons in time throughout the crop's global production regions using published data and feedback from local breeders. This information is used to calculate and map regionally specific chickpea bioclimatic variables such as flowering phase temperatures and the peak rate of growing season temperature change. Flowering phase temperatures <14 °C are uncommon. Mediterranean climates in southern Australia, Chile, California and Portugal tend to be cool during flowering (<15.4 °C), while much of WANA is moderate to warm (15.4–24.4 °C), with exceptions in coastal N Africa, the Nile valley and higher elevations in Morocco, the Balkans, central Afghanistan, NE and SW Iran. Ethiopia contains a wide range of flowering phase temperatures depending on altitude. In South Asia flowering phase temperatures tend to decrease with increasing latitude, with large cool regions in the Punjab, N Haryana, N Uttar Pradesh and the Nepali terai. Superimposing the peak rates of temperature change within the growing season identifies habitats which are likely to be consistently cool throughout the reproductive phase by eliminating regions with transient chilling stress, such as much of N South Asia. It is suggested that reproductive chilling tolerance is rare in chickpea because of the late Neolithic shift from autumn to spring sowing in WANA, and subsequent dissemination into predominantly moderate to warm flowering habitats with only transient low temperature stress. The search for reproductive chilling tolerance should concentrate on these relatively uncommon consistently cool habitats. These are not well represented in the world chickpea collection, a shortcoming which is exacerbated by the lack of passport data in regions of potential interest from Iran to Central Asia. An alternative strategy is to search for reproductive chilling tolerance in the wild Cicer species, which have maintained a winter annual lifecycle and appear to be more cold tolerant than the cultigen. This approach is limited by the lack of germplasm. Currently, there are <30 original wild accessions in the primary genepool of chickpea ( C. reticulatum, n = 18; C. echinospermum, n = 10) in the world's genebanks, so more collection is required.

Accessing speech data using strategic fixation

When users access information from text, they engage in strategic fixation, visually scanning the text to focus on regions of interest. However, because speech is both serial and ephemeral, it does not readily support strategic fixation. This paper describes two design principles, indexing and transcript-centric access that address the problem of speech access by supporting strategic fixation. Indexing involves users constructing external visual indices into speech. Users visually scan these indices to find information-rich regions of speech for more detailed processing and playback. Transcription involves transcribing speech using automatic speech recognition (ASR) and enriching that transcription with visual cues. The resulting enriched transcript is time-aligned to the original speech, allowing users to scan the transcript as a whole or the additional visual cues present in the transcript, to fixate and play regions of interest. We tested the effectiveness of these two approaches on a set of reference tasks derived from observations of current voicemail practice. A field trial evaluation of JotMail, an indexed-based interface similar to commercial unified messaging clients, showed that our approaches were effective in supporting speech scanning, information extraction and status tracking, but not archive management. However, users found it onerous to take manual notes with JotMail to provide effective retrieval indices. We therefore built SCANMail, a transcript-based interface that constructs indices automatically, using ASR to generate a transcript of the speech data. SCANMail also uses information extraction techniques to identify regions of potential interest, e.g. telephone numbers, within the transcript. Laboratory and field trials showed that SCANMail overcame most of the problems users reported with JotMail, supporting scanning, information extraction and archiving. Importantly, our evaluations showed that, despite errors, ASR transcripts provide a highly effective tool for browsing. Users exploited the enriched transcript to determine the gist of the underlying speech, and as a guide to identifying areas of speech that it was critical for them to play. Long-term field trials also showed the utility of transcripts to support notification and mobile access.

The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen.

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex. Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of sibling pairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

Chromosomal aberrations and bipolar affective disorder.

Chromosomal abnormalities associated with bipolar disorder may help in the localisation of susceptibility genes for bipolar illness by pinpointing 'candidate' regions of the genome for further study using molecular genetic methods. We review descriptions of chromosomal abnormalities in association with bipolar and related affective disorders and evaluate their relevance for localising susceptibility genes for bipolar disorder, using standardised criteria. We found 28 reports. We identified four genomic regions of potential interest: 11q21-25; 15q11-13; chromosome 21;Xq28. It is important that clinicians are able to recognise patients who may have chromosome abnormalities which could help in the localisation of susceptibility genes for psychiatric disorders. We suggest referral for specialist investigation and karyotyping, to a psychiatric genetics research group, of any patient with functional psychosis and one or more of the following: (a) a strong family history of functional psychosis; (b) mental retardation; (c) another disease known to be caused by a single gene; or (d) congenital abnormalities.

Multiple binding sites for nuclear factors in the 5′-upstream region of two α2u-globulin genes: Implications for hormone-regulated and tissue-specific control

In order to understand the tissue- and hormone-specific control of α 2u-globulin synthesis we isolated the 5′-upstream putative regulatory region of two α 2u-globulin genes: RAP 01 and RAO 01. Both clones seem to be expressed in rat liver. DNAseI footprinting analysis after incubation with rat liver nuclear extracts was used to identify regions of potential interest. Particular attention was paid to protected regions located in the neighbourhood of domains which, according to our previous studies, interact specifically with androgen- and glucocorticoid-receptor complexes. Fifteen DNAseI footprints could be mapped in clone RAO 01 (bp - 758 up to the cap site). Nineteen footprints were observed in the corresponding region of RAP 01. Differences in the footprinting patterns were mainly observed in the more distal regions. Our data confirm the presence in both clones of two binding sites for the liver enriched factor pseudo-NF1 and one site for C/EBP previously observed in other α 2u-globulin genes. In addition we have been able to demonstrate, in RAP 01 only, a binding site for transferrin-liver factor 1. No differences in footprinting patterns could be demonstrated using liver nuclear extracts derived from animals with a high hepatic expression of α 2u-globulins (normal male rats) and animals with low to absent expression (prepubertal rats, female rats, rats with the testicular feminization syndrome, diabetic rats and hypophysectomized animals). Transfection experiments indicate that a fragment of RAP 01 (bp −643 up to −617) is able to act as a glucocorticoid and as an androgen response element. Larger fragments of RAP 01 and fragments of RAO 01 are ineffective. It is concluded that the expression of individual α 2u-globulin genes is probably the result of combinatorial interactions of several trans-acting factors with appropriate cis-acting elements. Moreover, important sites for tissue-specific and hormone-regulated expression may be situated outside the regions investigated.

CHARACTERIZATION OF MHC ANCESTRAL HAPLOTYPES ASSOCIATED WITH INSULIN‐DEPENDENT DIABETES MELLITUS: EVIDENCE FOR INVOLVEMENT OF NON‐HLA GENES

Insulin-dependent diabetes mellitus (IDDM) is associated with several DR3- or DR4-containing ancestral haplotypes (AHs). Using pulsed field gel electrophoresis (PFGE), long range maps of 35 haplotypes have been derived and classified. Two diabetogenic DR3-containing AHs (8.1 and 18.2) possess deletions in the central non-HLA region; these have not been found on non-diabetogenic AHs tested to date. In addition, 8.1 and 18.2 also carry other deletions not found on other AHs. Three DR4 containing AH lack a Not I site, which may imply excision of an unidentified gene. These and other data suggest that deletions may be relevant to the pathogenesis of autoimmune disease, possibly through causing quantitative differences in autoimmune responses involved in IDDM. The MHC contains several regions of potential interest in relation to susceptibility to IDDM; these may explain the association with only certain DR3- and DR4-carrying AH and DR3,4 heterozygosity in terms of cis and trans interactions. On the other hand, the class II region may be particularly important in protection.

Rendering of the Shroud of Turin using sinusoidal pseudocolor and other image processing techniques

To help characterize noisy and subtle features in images, computers with graphics can be used to produce visual representations with a spectrum of perspectives. In this article, processed images of the Shroud of Turin—a 2000-year-old linen burial cloth—are computed, and they are presented with accompanying descriptions of patterns produced by the image processing. The images of the Shroud are created by using sinusoidal pseudocolor functions, and the resultant pictures reveal a beautiful, complex picture and help to differentiate various regions of potential interest. This paper differs from others in that it focuses on mathematical techniques for rendering this image which include unusual equations, shading, and convergence schemes.