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PubMedDate not supplied

Minimum-flip supertrees: complexity and algorithms.

The input to a supertree problem is a collection of phylogenetic trees that intersect pairwise in their leaf sets; the goal is to construct a single tree that retains as much as possible of the information in the input. This task is complicated by inconsistencies due to errors. We consider the case where the input trees are rooted and are represented by the clusters they exhibit. The problem is to find the minimum number of flips needed to resolve all inconsistencies, where each flip moves a taxon into or out of a cluster. We prove that the minimum-flip problem is NP-complete, but show that it is fixed-parameter tractable and give approximation algorithms for special cases.

Algorithms↗
PubMed2001

How proxies make decisions about research for patients with Alzheimer's disease.

We examined the proxy decision-making and informed consent processes for clinical research involving 49 patient-subjects with dementia in an outpatient setting by performing serial in-depth, structured, open-ended telephone interviews. Interviews were tape recorded and transcribed. Transcripts were then coded and analyzed. Although in all cases proxy consent was obtained for research from a legally authorized representative, proxies reported considerable ambiguity regarding who made the decision to participate in research, or to what degree the decision was that of the proxy or of the patient. Reasons proxies gave for participating in research included: hope of direct or indirect benefits to the patient, caregiver, or patient's descendents; desperation; trust in the investigator; belief in the goodness of research; and altruism. These reasons varied according to the type of research. For instance, in drug trials hope of direct benefit prevailed; in studies not evaluating a potential therapy more altruistic concerns predominated. Being a proxy decision maker for research can be burdensome. The degree of burden related to making a decision to participate in research seems influenced by a number of intersecting factors, most importantly, the risk and nature of the study, the extent to which patients were able to participate in the decision, and the duration and severity of dementia. Proxy decision-making concerning participation in research for patients with dementia can be a difficult task. The process might be improved by emphasizing that proxy consent is being sought because the nature of the patient's underlying medical condition can preclude the ability to make meaningful decisions. In addition, clinical researchers should recognize that giving proxy consent might place additional burdens on caregivers and discuss this explicitly when proxy consent is solicited.

Aged↗
PubMed1997

RNA fingerprinting displays UVB-specific disruption of transcriptional control in human melanocytes.

In mammalian cells, UV induces a limited set of early transcribed genes, which overlaps with the set of genes induced by tumor promoting drugs such as 12-O-tetradecanoyl phorbol-13-acetate (TPA). Among these are genes for transcription factors, the activation of which leads to complex secondary changes in expression of multiple target genes. How these delayed pleiotropic UV effects on transcription may contribute to initiation of melanoma skin cancer is poorly understood. We analyzed changes in the relative abundances of 1900 transcripts in newborn human melanocytes 8 h after treatment with UVB, TPA, and cycloheximide in all combinations, using RNA arbitrarily primed PCR for differential display. The relative abundances of 205 transcripts (11% of all transcripts surveyed) were altered by one or more of the treatment combinations. Fourteen of the 77 genes up-regulated by TPA were also up-regulated by UVB, but 60 of the TPA up-regulated genes were down-regulated by UVB, indicating both intersecting and independent signal transduction pathways for UVB and TPA. A number of UVB and TPA target genes were identified by cDNA cloning. Consistent with UVB induction of a partly transformed phenotype in mammalian cells, UVB antagonized the TPA-inducible expression of tumor-suppressive tropomyosin 3 mRNA. In addition, UVB may impair mitochondrial functioning and induce oxidative stress by strong down-regulation of mitochondrial transcription. Finally, increased expression of the dihydropteridine reductase gene, a major regulator of the cellular tetrahydrobiopterin pool, was linked to the UV pathway.

Carcinogens↗
PubMed2006

Global similarity and local divergence in human and mouse gene co-expression networks.

BACKGROUND: A genome-wide comparative analysis of human and mouse gene expression patterns was performed in order to evaluate the evolutionary divergence of mammalian gene expression. Tissue-specific expression profiles were analyzed for 9,105 human-mouse orthologous gene pairs across 28 tissues. Expression profiles were resolved into species-specific coexpression networks, and the topological properties of the networks were compared between species. RESULTS: At the global level, the topological properties of the human and mouse gene coexpression networks are, essentially, identical. For instance, both networks have topologies with small-world and scale-free properties as well as closely similar average node degrees, clustering coefficients, and path lengths. However, the human and mouse coexpression networks are highly divergent at the local level: only a small fraction (<10%) of coexpressed gene pair relationships are conserved between the two species. A series of controls for experimental and biological variance show that most of this divergence does not result from experimental noise. We further show that, while the expression divergence between species is genuinely rapid, expression does not evolve free from selective (functional) constraint. Indeed, the coexpression networks analyzed here are demonstrably functionally coherent as indicated by the functional similarity of coexpressed gene pairs, and this pattern is most pronounced in the conserved human-mouse intersection network. Numerous dense network clusters show evidence of dedicated functions, such as spermatogenesis and immune response, that are clearly consistent with the coherence of the expression patterns of their constituent gene members. CONCLUSION: The dissonance between global versus local network divergence suggests that the interspecies similarity of the global network properties is of limited biological significance, at best, and that the biologically relevant aspects of the architectures of gene coexpression are specific and particular, rather than universal. Nevertheless, there is substantial evolutionary conservation of the local network structure which is compatible with the notion that gene coexpression networks are subject to purifying selection.

Animals↗
PubMed1996

Primary pulmonary sarcoma with morphologic features of monophasic synovial sarcoma and chromosome translocation t(X; 18).

The authors report an unusual spindle cell sarcoma that arose in the lung of a 12-year-old girl. This tumor had histologic, immunophenotypic, and ultrastructural features consistent with monophasic fibrous synovial sarcoma. These features included a growth pattern of densely packed spindle cells in irregularly intersecting, broad fascicles, diffuse vimentin immunoreactivity, and focal expression of epithelial membrane antigen and S100 protein. This diagnosis was further supported by cytogenetic studies showing the specific t(X; 18) chromosomal translocation associated with synovial sarcoma. This balanced translocation appears to be an essentially universal characteristic of these sarcomas, regardless of histologic subtype or site of origin. The constellation of morphologic and cytogenetic findings in this case firmly establishes synovial sarcoma as a subtype of pulmonary spindle cell sarcomas. The distinctive features of these neoplasms allow them to be distinguished from a variety of primary and metastatic malignancies in the lung.

Child↗
PubMed2003

Sequence elements outside the hammerhead ribozyme catalytic core enable intracellular activity.

The hammerhead ribozyme (HHRz) is a small, naturally occurring ribozyme that site-specifically cleaves RNA and has long been considered a potentially useful tool for gene silencing. The minimal conserved HHRz motif derived from natural sequences consists of three helices that intersect at a highly conserved catalytic core of 11 nucleotides. The presence of this motif is sufficient to support cleavage at high Mg2+ concentrations, but not at the low Mg2+ concentrations characteristic of intracellular environments. Here we demonstrate that natural HHRzs require the presence of additional nonconserved sequence elements outside of the conserved catalytic core to enable intracellular activity. These elements may stabilize the HHRz in a catalytically active conformation via tertiary interactions. HHRzs stabilized by these interactions cleave efficiently at physiological Mg2+ concentrations and are functional in vivo. The proposed role of these tertiary interacting motifs is supported by mutational, functional, structural and molecular modeling analysis of natural HHRzs.

Amino Acid Motifs↗
PubMed2005

WebGestalt: an integrated system for exploring gene sets in various biological contexts.

High-throughput technologies have led to the rapid generation of large-scale datasets about genes and gene products. These technologies have also shifted our research focus from 'single genes' to 'gene sets'. We have developed a web-based integrated data mining system, WebGestalt (http://genereg.ornl.gov/webgestalt/), to help biologists in exploring large sets of genes. WebGestalt is composed of four modules: gene set management, information retrieval, organization/visualization, and statistics. The management module uploads, saves, retrieves and deletes gene sets, as well as performs Boolean operations to generate the unions, intersections or differences between different gene sets. The information retrieval module currently retrieves information for up to 20 attributes for all genes in a gene set. The organization/visualization module organizes and visualizes gene sets in various biological contexts, including Gene Ontology, tissue expression pattern, chromosome distribution, metabolic and signaling pathways, protein domain information and publications. The statistics module recommends and performs statistical tests to suggest biological areas that are important to a gene set and warrant further investigation. In order to demonstrate the use of WebGestalt, we have generated 48 gene sets with genes over-represented in various human tissue types. Exploration of all the 48 gene sets using WebGestalt is available for the public at http://genereg.ornl.gov/webgestalt/wg_enrich.php.

Computer Graphics↗
PubMed2003

Molecular pathways of neurodegeneration in Parkinson's disease.

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.

Animals↗
PubMed2004

Physical and functional association of RNA polymerase II and the proteasome.

Recent studies from a number of laboratories have revealed a surprising number of connections between RNA polymerase II transcription and the ubiquitin/proteasome pathway. We now find yet another intersection of these pathways by showing that the 26S proteasome associates with regions of the GAL1, GAL10, and HSP82 genes, including the 3' ends, in a transcription-dependent fashion. The appearance of the proteasome on these inducible genes correlates with both the accumulation of transcripts and the buildup of RNA polymerase II complexes in the same region. Furthermore, the 26S proteasome and RNA polymerase II coimmunoprecipitate, and inhibition of 26S proteolytic activity leads to increased read through of a transcription termination site. We suggest that the proteasome is generally recruited to the DNA at sites of stalled RNA polymerase and may act to resolve these complexes.

Cysteine Endopeptidases↗
PubMed2004

Molecular diversity of astrocytes with implications for neurological disorders.

The astrocyte represents the most abundant yet least understood cell type of the CNS. Here, we use a stringent experimental strategy to molecularly define the astrocyte lineage by integrating microarray datasets across several in vitro model systems of astrocyte differentiation, primary astrocyte cultures, and various astrocyterich CNS structures. The intersection of astrocyte data sets, coupled with the application of nonastrocytic exclusion filters, yielded many astrocyte-specific genes possessing strikingly varied patterns of regional CNS expression. Annotation of these astrocyte-specific genes provides direct molecular documentation of the diverse physiological roles of the astrocyte lineage. This global perspective in the normal brain also provides a framework for how astrocytes may participate in the pathogenesis of common neurological disorders like Alzheimer's disease, Parkinson's disease, stroke, epilepsy, and primary brain tumors.

Animals↗
PubMed2003

Putting data integration into practice: using biomedical terminologies to add structure to existing data sources.

A major purpose of biomedical terminologies is to provide uniform concept representation, allowing for improved methods of analysis of biomedical information. While this goal is being realized in bioinformatics, with the emergence of the Gene Ontology as a standard, there is still no real standard for the representation of clinical concepts. As discoveries in biology and clinical medicine move from parallel to intersecting paths, standardized representation will become more important. A large portion of significant data, however, is mainly represented as free text, upon which conducting computer-based inferencing is nearly impossible. In order to test our hypothesis that existing biomedical terminologies, specifically the UMLS Metathesaurus and SNOMED CT, could be used as templates to implement semantic and logical relationships over free text data that is important both clinically and biologically, we chose to analyze OMIM (Online Mendelian Inheritance in Man). After finding OMIM entries' conceptual equivalents in each respective terminology, we extracted the semantic relationships that were present and evaluated a subset of them for semantic, logical, and biological legitimacy. Our study reveals the possibility of putting the knowledge present in biomedical terminologies to its intended use, with potentially clinically significant consequences.

Databases, Genetic↗
PubMed1998

Traffic into the prevacuolar/endosomal compartment of Saccharomyces cerevisiae: a VPS45-dependent intracellular route and a VPS45-independent, endocytic route.

The vps (vacuolar protein sorting) mutants have been used to dissect and characterize the vacuolar biogenesis pathway in the yeast Saccharomyces cerevisiae. The vps mutants were isolated through their loss of ability to correctly sort the vacuolar hydrolase CPY, which travels from Golgi membranes to the vacuole through a prevacuolar compartment. Over 50 VPS genes have been divided into 6 classes according to vacuolar morphology. Mutations in any one of the class E VPS genes, such as VPS27, lead to an exaggerated form of the prevacuolar compartment. This class E compartment contains endocytosed proteins as well as proteins en route to the vacuole, and is thus taken to represent an intersection point between the endocytic and biosynthetic pathways. Mutations in the class D gene VPS45 can be used to define a second transport intermediate along the vacuolar biogenesis pathway, Golgi-derived transport vesicles carrying vacuolar membrane proteins on their way to the vacuole. Here we demonstrate that the Sec1p-like protein Vps45p is required for the fusion of Golgi-derived vesicles with the prevacuolar compartment indicating that VPS45 functions before VPS27 in the vacuolar biogenesis pathway. In addition, we show that VPS45 function is not required for the delivery of endocytosed proteins to the prevacuolar compartment from the plasma membrane suggesting that the function of Vps45p is restricted to a single vesicular pathway.

Biological Transport↗
PubMed2004

Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression.

Many studies have used DNA microarrays to identify the gene expression signatures of human cancer, yet the critical features of these often unmanageably large signatures remain elusive. To address this, we developed a statistical method, comparative metaprofiling, which identifies and assesses the intersection of multiple gene expression signatures from a diverse collection of microarray data sets. We collected and analyzed 40 published cancer microarray data sets, comprising 38 million gene expression measurements from >3,700 cancer samples. From this, we characterized a common transcriptional profile that is universally activated in most cancer types relative to the normal tissues from which they arose, likely reflecting essential transcriptional features of neoplastic transformation. In addition, we characterized a transcriptional profile that is commonly activated in various types of undifferentiated cancer, suggesting common molecular mechanisms by which cancer cells progress and avoid differentiation. Finally, we validated these transcriptional profiles on independent data sets.

Cell Transformation, Neoplastic↗
PubMed2001

Identifying marker genes in transcription profiling data using a mixture of feature relevance experts.

Transcription profiling experiments permit the expression levels of many genes to be measured simultaneously. Given profiling data from two types of samples, genes that most distinguish the samples (marker genes) are good candidates for subsequent in-depth experimental studies and developing decision support systems for diagnosis, prognosis, and monitoring. This work proposes a mixture of feature relevance experts as a method for identifying marker genes and illustrates the idea using published data from samples labeled as acute lymphoblastic and myeloid leukemia (ALL, AML). A feature relevance expert implements an algorithm that calculates how well a gene distinguishes samples, reorders genes according to this relevance measure, and uses a supervised learning method [here, support vector machines (SVMs)] to determine the generalization performances of different nested gene subsets. The mixture of three feature relevance experts examined implement two existing and one novel feature relevance measures. For each expert, a gene subset consisting of the top 50 genes distinguished ALL from AML samples as completely as all 7,070 genes. The 125 genes at the union of the top 50s are plausible markers for a prototype decision support system. Chromosomal aberration and other data support the prediction that the three genes at the intersection of the top 50s, cystatin C, azurocidin, and adipsin, are good targets for investigating the basic biology of ALL/AML. The same data were employed to identify markers that distinguish samples based on their labels of T cell/B cell, peripheral blood/bone marrow, and male/female. Selenoprotein W may discriminate T cells from B cells. Results from analysis of transcription profiling data from tumor/nontumor colon adenocarcinoma samples support the general utility of the aforementioned approach. Theoretical issues such as choosing SVM kernels and their parameters, training and evaluating feature relevance experts, and the impact of potentially mislabeled samples on marker identification (feature selection) are discussed.

Acute Disease↗
PubMed2004

Current debates in antiphospholipid syndrome: the acquired antibody-mediated thrombophilia.

Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term "APL antibodies" represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anti-coagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.

Animals↗
PubMed2005

Bacillus subtilis ilvB operon: an intersection of global regulons.

The genes of the major Bacillus subtilis operon (ilvB) for biosynthesis of branched-chain amino acids are subject to multiple mechanisms of regulation. The global regulatory proteins CodY and TnrA bind upstream of the transcription start site and are likely to control transcription initiation, leucine-specific tRNA regulates transcriptional elongation, and unknown factors differentially cleave the full-length mRNA. Another global regulator, CcpA, known to be required for ilvB transcription, was shown here to act directly at the ilvB promoter by a novel mechanism. Although CcpA was able to bind to the ilvB promoter region, it stimulated transcription significantly only when CodY was present, suggesting that CcpA acts primarily by interfering with repression by CodY. Additionally, CcpA was shown to control indirectly the expression of other CodY-regulated target genes, apparently by altering the intracellular level of branched-chain amino acids.

Bacillus subtilis↗
PubMed2000

Comparative microarray analysis of gene expression during apoptosis-induction by growth factor deprivation or protein kinase C inhibition.

The transcriptional response of mouse pro-B cells to two different apoptotic stimuli was investigated. First, interleukin-3 (IL-3) deprivation was used to trigger programmed cell death in IL-3 dependent FL5.12 cells. Alternatively, cells were treated with the protein kinase C (PKC) inhibitor staurosporine. The temporal pattern of gene expression was followed with cDNA microarrays, covering over 8700 different mouse cDNA sequences corresponding to approximately 7900 unique genes. Messenger RNA levels of 315 genes were found to be regulated by more than twofold upon IL-3 removal, while 125 genes reacted to staurosporine treatment. Cross-comparison revealed an intersection of 34 genes similarly regulated in both pathways and thus representing candidates for common apoptosis regulators. For many expressed sequence tags (ESTs) our data suggest for the first time functions in the control of apoptosis, stress response or the cell cycle. IL-3 removal led to the repression of genes required for proliferation and to the induction of genes, linked to apoptotic and signaling pathways. Staurosporine caused predominantly activation of genes, some of which had previously been described to be involved in inflammation. Our findings indicate that cellular responses to both apoptotic stimuli influence various physiological pathways which had not previously been known to be linked.

Animals↗
PubMed2000

The developing brain and the environment: an introduction.

mental retardation: timing and thresholds; (italic)b(/italic)) endocrine dysfunction and developmental disabilities: dose and target implications; (italic)c(/italic)) attention-deficit disorder-ADHD and learning disabilities; and (italic)d(/italic)) new horizons: extending the boundaries. Support for the Rochester conference came from both public and private sources. The National Institute of Environmental Health Sciences (NIEHS), the National Institute of Child Health and Human Development, and the EPA represented the federal government. The conference also received grants from several foundations: the Jennifer Altman Foundation, the Heinz Family Foundation, the National Alliance for Autism Research, the Violence Research Foundation, the Wacker Foundation, and the Winslow Foundation. The second of these conferences helped launch a new Center for Children's Health and the Environment at the Mount Sinai School of Medicine. It was held in New York City on 24-25 May 1999, and was convened specifically to consider the intersection between neurodevelopmental impairment, environmental chemicals, and prevention. Over 300 health scientists, pediatricians, and public health professionals examined the growing body of evidence linking environmental toxins to neurobehavioral disorders. The conference title was Environmental Influences on Children: Brain, Development, and Behavior. The conference began by reviewing well-known examples of deleterious effects of environmental chemicals, including lead and PCBs, on children's brains. The conferees then considered the potential impact of environmental chemicals on neurological disorders with particular focus on ADHD, autism, and Parkinson's disease. The inclusion of Parkinson's disease was intended to signal the notion that exposures in early life may have an influence on the evolution of neurological disease in later life. Support for the Mount Sinai conference came from the Superfund Basic Research Program (NIEHS); The Pew Charitable Trusts; the Institute for Health and the Environment at the University of Albany School of Public Health; the Agency for Toxic Substances and Disease Research (ATSDR); the Ambulatory Pediatric Association; Myron A. Mehlman, PhD; the National Center for Environmental Assessment (EPA); the National Center for Environmental Health (CDC); the National Institute of Child Health and Human Development; the Office of Children's Health Protection (EPA); Physicians for Social Responsibility; The New York Academy of Medicine; The New York Community Trust; and the Wallace Genetic Foundation. The impact of environmental toxins on children's health has become a topic of major concern in the federal government. Eight new research centers in children's environmental health have been established in the past 2 years with joint funding from EPA and NIEHS. Clinical units that specialize in the treatment of children with environmentally induced illness have been developed across the nation with grant support from ATSDR. The American Academy of Pediatrics has just published its (italic)Handbook of Pediatric Environmental Health (/italic)((italic)17(/italic)), the "Green Book," which is available to pediatricians throughout the Americas. Children's environmental health has climbed to a critical position as we launch the new millennium. This monograph marks a significant milestone in the evolution of this emerging discipline.

Brain↗