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PubMed2006

PathSys: integrating molecular interaction graphs for systems biology.

BACKGROUND: The goal of information integration in systems biology is to combine information from a number of databases and data sets, which are obtained from both high and low throughput experiments, under one data management scheme such that the cumulative information provides greater biological insight than is possible with individual information sources considered separately. RESULTS: Here we present PathSys, a graph-based system for creating a combined database of networks of interaction for generating integrated view of biological mechanisms. We used PathSys to integrate over 14 curated and publicly contributed data sources for the budding yeast (S. cerevisiae) and Gene Ontology. A number of exploratory questions were formulated as a combination of relational and graph-based queries to the integrated database. Thus, PathSys is a general-purpose, scalable, graph-data warehouse of biological information, complete with a graph manipulation and a query language, a storage mechanism and a generic data-importing mechanism through schema-mapping. CONCLUSION: Results from several test studies demonstrate the effectiveness of the approach in retrieving biologically interesting relations between genes and proteins, the networks connecting them, and of the utility of PathSys as a scalable graph-based warehouse for interaction-network integration and a hypothesis generator system. The PathSys's client software, named BiologicalNetworks, developed for navigation and analyses of molecular networks, is available as a Java Web Start application at http://brak.sdsc.edu/pub/BiologicalNetworks.

Computer Graphics↗
PubMed2004

Structural analysis of disease-causing mutations in the P-subfamily of forkhead transcription factors.

Mutations in a number of forkhead transcription factors are associated with the development of inherited diseases in humans. Two closely related genes, FOXP2 and FOXP3, are implicated in two completely different human disorders. A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. Homology model building techniques were used to generate atomic structures of FOXP2 and FOXP3, using the solution structures of the forkhead domain of the adipocyte-transcription factor FREAC-11 and AFX as templates. The impact of these disease-causing missense mutations on the three-dimensional structure, stability, and surface electrostatic charge distribution of the forkhead domains is examined here. The missense mutations R553H in FOXP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains.

Amino Acid Sequence↗
PubMed2007

Analogy between language and biology: a functional approach.

We adopt here a functional approach to the classical comparison between language and biology. We first parallel events which have a functional signification in each domain, by matching the utterance of a sentence with the release of a protein. The meaning of a protein is then defined by analogy as "the constant contribution of the biochemical material composing the protein to the effects produced by any release of the protein". The proteome of an organism corresponds to an I-language (the idiolect of an individual), and the proteome of a species is equivalent to an E-language (a language in the common sense). Proteins and sentences are both characterized by a complex hierarchical structure, but the language property of 'double articulation' has no equivalent in the biological domain in this analogy, contrary to previous proposals centered on the genetic code. Besides, the same intimate relation between structure and meaning holds in both cases (syntactic structure for sentences and three-dimensional conformation for proteins). An important disanalogy comes from the combinatorial power of language which is not shared by the proteome as a whole, but it must be noted that the immune system possesses interesting properties in this respect. Regarding evolutionary aspects, the analogy still works to a certain extent. Languages and proteomes can be both considered as belonging to a general class of systems, that we call "productive self-reproductive systems", characterized by the presence of two dynamics: a fast dynamics in an external domain where functional events occur (productive aspect), and a slow dynamics responsible for the evolution of the system itself, driven by the feed-back of events related to the reproduction process.

Animals↗
PubMed2025

Deep learning-based annotation of plant abiotic stress resistance genes for crops.

The declining costs of DNA sequencing have expanded genomic data, crucial for understanding plant abiotic stress responses and crop improvement. However, accurate gene annotation remains challenging. To address this limitation, we propose the PASRGA, a deep learning approach that leverages transfer learning and contrastive learning to annotate genes related to drought, salt, cold, and UV resistance. PASRGA achieves high F1-scores, area under the receiver operating characteristic (AUROC), area under the precision-recall curve (AUPRC), and Matthews correlation coefficient (MCC) in annotating stress resistance genes, significantly outperforming the general protein annotation model CLEAN, the plant phosphatase gene annotation model PF-NET, the top-ranked model in the CAFA5 challenge NetGO 4.0, and four traditional machine learning methods. Its effectiveness was further validated with a salt stress treatment experiment in Eutrema salsugineum. To facilitate crop breeding practices, we utilized PASRGA to annotate the genomes of 17 major crops. To improve accessibility and utility, we incorporated both manually curated and PASRGA-predicted gene data, together with the PASRGA tool, into the PlantASRG database (https://bioinfor.nefu.edu.cn/PlantASRG/). This comprehensive resource aims to support crop breeding initiatives and ensure food security.

Crops, Agricultural↗
PubMed2003

What can developmental disorders tell us about the neurocomputational constraints that shape development? The case of Williams syndrome.

The uneven cognitive phenotype in the adult outcome of Williams syndrome has led some researchers to make strong claims about the modularity of the brain and the purported genetically determined, innate specification of cognitive modules. Such arguments have particularly been marshaled with respect to language. We challenge this direct generalization from adult phenotypic outcomes to genetic specification and consider instead how genetic disorders provide clues to the constraints on plasticity that shape the outcome of development. We specifically examine behavioral studies, brain imaging, and computational modeling of language in Williams syndrome but contend that our theoretical arguments apply equally to other cognitive domains and other developmental disorders. While acknowledging that selective deficits in normal adult patients might justify claims about cognitive modularity, we question whether similar, seemingly selective deficits found in genetic disorders can be used to argue that such cognitive modules are prespecified in infant brains. Cognitive modules are, in our view, the outcome of development, not its starting point. We note that most work on genetic disorders ignores one vital factor, the actual process of ontogenetic development, and argue that it is vital to view genetic disorders as proceeding under different neurocomputational constraints, not as demonstrations of static modularity.

Cognition Disorders↗
PubMed2004

Gene name ambiguity of eukaryotic nomenclatures.

MOTIVATION: With more and more scientific literature published online, the effective management and reuse of this knowledge has become problematic. Natural language processing (NLP) may be a potential solution by extracting, structuring and organizing biomedical information in online literature in a timely manner. One essential task is to recognize and identify genomic entities in text. 'Recognition' can be accomplished using pattern matching and machine learning. But for 'identification' these techniques are not adequate. In order to identify genomic entities, NLP needs a comprehensive resource that specifies and classifies genomic entities as they occur in text and that associates them with normalized terms and also unique identifiers so that the extracted entities are well defined. Online organism databases are an excellent resource to create such a lexical resource. However, gene name ambiguity is a serious problem because it affects the appropriate identification of gene entities. In this paper, we explore the extent of the problem and suggest ways to address it. RESULTS: We obtained gene information from 21 organisms and quantified naming ambiguities within species, across species, with English words and with medical terms. When the case (of letters) was retained, official symbols displayed negligible intra-species ambiguity (0.02%) and modest ambiguities with general English words (0.57%) and medical terms (1.01%). In contrast, the across-species ambiguity was high (14.20%). The inclusion of gene synonyms increased intra-species ambiguity substantially and full names contributed greatly to gene-medical-term ambiguity. A comprehensive lexical resource that covers gene information for the 21 organisms was then created and used to identify gene names by using a straightforward string matching program to process 45,000 abstracts associated with the mouse model organism while ignoring case and gene names that were also English words. We found that 85.1% of correctly retrieved mouse genes were ambiguous with other gene names. When gene names that were also English words were included, 233% additional 'gene' instances were retrieved, most of which were false positives. We also found that authors prefer to use synonyms (74.7%) to official symbols (17.7%) or full names (7.6%) in their publications. CONTACT: lifeng.chen@dbmi.columbia.edu

Abstracting and Indexing↗
PubMed2003

Mutually symmetric and complementary triplets: differences in their use distinguish systematically between coding and non-coding genomic sequences.

The general property of asymmetry in word use in meaningful texts written in a variety of languages, motivates a quantification of the differences in the use of mutually symmetric triplets in genomic sequences. When this is done in the three reading frames, high values found for one of them are used as indication that the sequence is coding for a protein. Moreover, a similar quantification of the differences in the use of complementary triplets is introduced, again with predictive power of the coding character of a sequence. This method reflects the non-equivalence between sense and anti-sense strand of a coding segment. In both approaches, "linguistic asymmetry" in coding sequences is related to the form of the genetic code and to the bias in codon usage and amino acid use skews.

Algorithms↗
PubMedDate not supplied

Dietary protein and blood pressure.

OBJECTIVE: - To review published and presented data on the relationship between dietary protein and blood pressure in humans and animals. DATA SOURCES: - Bibliographies from review articles and books on diet and blood pressure that had references to dietary protein. The bibliographies were supplemented with computerized MEDLINE search restricted to English language and abstracts presented at epidemiologic meetings. STUDY SELECTION: - Observational and intervention studies in humans and experimental studies in animals. DATA EXTRACTION: - In human studies, systolic or diastolic blood pressure were outcome measures, and dietary protein was measured by dietary assessment methods or by urine collections. In animal studies, blood pressure and related physiological effects were outcome measures, and experimental treatment included protein or amino acids. DATA SYNTHESIS: - Historically, dietary protein has been thought to raise blood pressure; however, studies conducted in Japan raised the possibility of an inverse relationship. Data analyses from subsequent observational studies in the United States and elsewhere have provided evidence of an inverse relationship between protein and blood pressure. However, intervention studies have mostly found no significant effects of protein on blood pressure. Few animal studies have specifically examined the effects of increased dietary protein on blood pressure. CONCLUSIONS: - Because of insufficient data and limitations in previous investigations, better controlled and adequately powered human studies are needed to assess the effect of dietary protein on blood pressure. In addition, more research using animal models, in which experimental conditions are highly controlled and detailed mechanistic studies can be performed, is needed to help provide experimental support for or against the protein-blood pressure hypothesis.

Animals↗
PubMed2004

MAVL and StickWRLD: visually exploring relationships in nucleic acid sequence alignments.

Many powerful tools have been created to detect and describe the similarities between nucleic acid or protein sequences. Frequently these take the form of a sequence consensus, expressing simple most popular positional identities, positional identities with allowances for varying positions or some type of statistical description of the positional frequency characteristics of the defining sequence family. Despite the fact that some provide intuitively interpretable descriptions of the consensuses themselves, they typically do not give the viewer any information about regions of the sequence that might have inter-positional dependencies, and that therefore do not obey a strict consensus behavior. Herein, we present MAVL (Multiple Alignment Variation Linker) and StickWRLD. MAVL is our web-based application for detecting and displaying both positive and negative inter-positional correlations in nucleic acid sequences. MAVL examines all positional pairs in each of a collection of pre-aligned sequences and determines any pairs that occur with either greater or lesser frequency than a positional frequency matrix would predict. These data are then composited into a StickWRLD representation and supplied back to the user as a VRML (virtual reality modeling language) file. MAVL and StickWRLD can be accessed at http://www.microbial-pathogenesis.org/stickwrld/. A tutorial that explains MAVL features and demonstrates typical user interactions with StickWRLD graphs is available at http://www.microbial-pathogenesis.org/stickwrld/tutorial/sticktut2.html. This tutorial is quite large; please be patient while it loads.

Algorithms↗
PubMed2005

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While the majority of children with nephrotic syndrome respond to corticosteroids, 70% experience a relapsing course. Corticosteroid usage has reduced the mortality rate to around 3%, however they have known serious adverse effects. OBJECTIVES: To determine the benefits and harms of corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Renal Group Specialised Register, MEDLINE and EMBASE without language restriction, reference lists of articles, abstracts from conference proceedings and contact with known investigators. Date of most recent search: October 2004 SELECTION CRITERIA: Randomised controlled trials performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent, with outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI).Meta-regression was used to explore potential between-study differences due to baseline risk of relapse, study quality and interventions. MAIN RESULTS: Nineteen trials were identified. Six trials comparing two months of prednisone with three months or more in the first episode showed longer duration significantly reduced the risk of relapse at 12 to 24 months (RR 0.70; 95% CI 0.58 to 0.84). There was an inverse linear relationship between treatment duration and risk of relapse (RR = 1.26 - 0.112 duration; P = 0.03). There was a significant reduction in the number of frequent relapsers and the mean relapse rate/patient/year. Deflazacort was significantly more effective in maintaining remission than prednisone in children who frequently relapsed (RR 0.44; 95% CI 0.25 to 0.78). There were no increases in adverse events. AUTHORS' CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment For a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate-day therapy for six months would reduce the number of children relapsing by 33%. Deflazacort deserves further study for frequent relapsers.

Adolescent↗
PubMedDate not supplied

A model program for providing health services for migrant farmworker mothers and children.

A bilingual, multidisciplinary team of health professionals collaborated with a migrant health center in North Carolina to develop a model program to deliver primary health care services to migrant farmworker women and children. The program included case finding and outreach, coordination of maternal and child health services locally as well as interstate, and innovative health education programming. Data were collected on the health status of 359 pregnant migrant farmworker women and 560 children, ages birth to 5 years, the majority of Mexican descent, who received primary care services at the center. The mean age of the women was 23.1 years and their mean gravidity was 2.9. Dietary assessments showed that the protein intakes of most met or exceeded the U.S. Recommended Dietary Allowances, but their consumption of foods in the milk-dairy group and the fruit-vegetable group was below recommended standards. Low hematocrit was a common problem among the women (43 percent) and, to a lesser extent, among the children (26 percent). Among the infants and children, 18 percent were obese. Black American women had the highest proportion of low birth weight infants. The project emphasized coordinated services for migrant farmworker mothers and children, such as transportation services, language translation, followup, and advocacy. An outreach strategy involved case finding, home visits, and services by lay health advisors. By the third year of the project, there were increases in the average number of prenatal visits, the proportion of women entering prenatal care in their first trimester, and in the use of well-child services. The project demonstrated effective methods for delivering culturally appropriate health care services to migrant farmworkermothers and children using bilingual public health professionals.

Adult↗
PubMed2006

Proteome informatics II: bioinformatics for comparative proteomics.

The present review attempts to cover the most recent initiatives directed towards representing, storing, displaying and processing protein-related data suited to undertake "comparative proteomics" studies. Data interpretation is brought into focus. Efforts invested into analysing and interpreting experimental data increasingly express the need for adding meaning. This trend is perceptible in work dedicated to determining ontologies, modelling interaction networks, etc. In parallel, technical advances in computer science are spurred by the development of the Web and the growing need to channel and understand massive volumes of data. Biology benefits from these advances as an application of choice for many generic solutions. Some examples of bioinformatics solutions are discussed and directions for on-going and future work conclude the review.

Algorithms↗
PubMed1997

Definite-clause grammars for the analysis of cis-regulatory regions in E. coli.

Based on an extensive collection of sigma 70 associated regulatory mechanisms, a grammatical model has been constructed that define the functional positions and combinations of sites within DNA regulatory regions. The syntactic rules and the dictionary implemented in a Prolog program were coupled to consensus matrices used as "sensors" to integrate a syntactic recognizer. A systematic comparison between the syntactic recognizer and the standard weight matrix methodology is presented using 12 regulatory proteins and the whole collection of about 130 sigma 70 DNA regulatory regions. On the average an increased sensitivity of 5 to 10 fold is obtained with this novel approach.

Binding Sites↗
PubMed2000

The new architectonics: an invitation to structural biology.

The philosophy of art might offer an epistemological basis for talking about the complexity of biological molecules in a meaningful way. The analysis of artistic compositions requires the resolution of intrinsic tensions between disparate sensory categories-color, line and form-not unlike those encountered in looking at the surfaces of protein molecules, where charge, polarity, hydrophobicity, and shape compete for our attentions. Complex living systems exhibit behaviors such as contraction waves moving along muscle fibers, or shivers passing through the growth cones of migrating neurons, that are easy to describe with common words, but difficult to explain in terms of the language of chemistry. The problem follows from a lack of everyday experience with processes that move towards equilibrium by switching between crystalline order and chain-like disorder, a commonplace occurrence in the submicroscopic world of proteins. Since most of what is understood about protein function comes from studies of isolated macromolecules in solution, a serious gap exists between what we know and what we would like to know about organized biological systems. Closing this gap can be achieved by recognizing that protein molecules reside in gradients of Gibbs free energy, where local forces and movements can be large compared with Brownian motion. Architectonics, a term borrowed from the philosophical literature, symbolizes the eventual union of the structure of theories-how our minds construct the world-with the theory of structures-or how stability is maintained in the chaotic world of microsystems.

History, 20th Century↗
PubMed1988

Classification of the European language families by genetic distance.

Genetic distances among speakers of the European language families were computed by using gene-frequency data for human blood group antigens, enzymes, and proteins of 26 genetic systems. Each system was represented by a different subset of 3369 localities across Europe. By subjecting the matrix of distances to numerical taxonomic procedures, we obtained a grouping of the language families of Europe by their genetic distances as contrasted with their linguistic relationships. The resulting classification largely reflects geographic propinquity rather than linguistic origins. This is evidence for the primary importance of short-range interdemic gene flow in shaping the modern gene pools of Europe. Yet, some language families--i.e., Basque, Finnic (including Lappish), and Semitic (Maltese)--have distant genetic relationships with their geographic neighbors. These results indicate that European gene pools still reflect the remote origins of some ethnic units subsumed by these major linguistic groups.

Ethnicity↗
PubMed2005

Review article: the potential of combinational regimen with non-steroidal anti-inflammatory drugs in the chemoprevention of colorectal cancer.

Non-steroidal anti-inflammatory drugs are chemopreventive agents in colorectal cancer. Non-steroidal anti-inflammatory drugs do not, however, offer complete protection against adenoma and carcinoma development. There is increasing interest in combining non-steroidal anti-inflammatory drugs with agents that target specific cell signalling pathways in malignant and premalignant cells. This review aims to describe the current knowledge regarding the efficacy of peroxisome proliferator-activated receptor-gamma ligands, cholesterol synthesis inhibitors (statins), epidermal growth factor signalling inhibitors and tumour necrosis factor-related apoptosis-inducing ligand against colorectal neoplasms and the rationale for combining these drugs with non-steroidal anti-inflammatory drugs to improve efficacy in the chemoprevention of colorectal cancer, a PUBMED computer search of the English language literature was conducted to identify relevant papers published before July 2004. Peroxisome proliferator-activated receptor-gamma ligands and statins, both in clinical use, reduce the growth rate of human colon cancer cells in vitro and in rodents models. In vitro, preclinical in vivo and clinical studies have shown efficacy of epidermal growth factor signalling inhibition in colorectal cancer. In vitro, tumour necrosis factor-related apoptosis-inducing ligand induces apoptosis in human colon cancer cells, but not in normal cells. These drugs have all been shown to interact with non-steroidal anti-inflammatory drugs in colorectal cancer cells and/or in rodent models. Combinational regimen are a promising strategy for the chemoprevention of colorectal cancer and should be further explored.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. About 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus and osteoporosis. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. The aim of this systematic review is to assess the benefits and harms of corticosteroid therapy in treating children with nephrotic syndrome. OBJECTIVES: To determine the benefits and harms of different corticosteroid regimes in preventing relapse in children with steroid responsive nephrotic syndrome (SRNS). SEARCH STRATEGY: Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, Medline, Embase, reference lists of articles, abstracts from proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SRNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk RR, risk difference RD) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. MAIN RESULTS: Twelve trials were identified. A meta-analysis of five trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (relative risk 0.73; 95% CI 0.60,0.89) without an increase in adverse events. There was an inverse linear relationship (RR = 1.382 (SE 0.215) - 0.133 duration (SE 0.048); r2 = 0.66; p = 0.05) between the duration of treatment and risk of relapse. The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25, 0.78). REVIEWER'S CONCLUSIONS: From this meta-analysis of randomised controlled trials it can be concluded that children in their first episode of nephrotic syndrome should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 40%. In children who relapse frequently, deflazacort deserves further study.

Adolescent↗
PubMed1997

Genetic structure of the indigenous populations of Siberia.

This study explores the genetic structure of Siberian indigenous populations on the basis of standard blood group and protein markers and DNA variable number of tandem repeats (VNTR) variation. Four analytical methods were utilized in this study: Harpending and Jenkin's R-matrix; Harpending and Ward's method of correlating genetic heterozygosity (H) to the distance from the centroid of the gene frequency array (rii); spatial autocorrelation, and Mantel tests. Because of the underlying assumptions of the various methods, the numbers of populations used in the analyses varied from 15 to 62. Since spatial autocorrelation is based upon separate correlations between alleles, a larger number of standard blood markers and populations were used. Fewest Siberian populations have been sampled for VNTRs, thus, only a limited comparison was possible. The four analytical procedures employed in this study yielded complementary results suggestive of the effects of unique historical events, evolutionary forces, and geography on the distribution of alleles in Siberian indigenous populations. The principal components analysis of the R-matrix demonstrated the presence of populational clusters that reflect their phylogenetic relationship. Mantel comparisons of matrices indicate that an intimate relationship exists between geography, languages, and genetics of Siberian populations. Spatial autocorrelation patterns reflect the isolation-by-distance model of Malecot and the possible effects of long-distance migration.

ABO Blood-Group System↗