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PubMedDate not supplied

[FOXP2: from the specific disorder to the molecular biology of language. II. Implications for the ontogenesis and phylogenesis of language].

INTRODUCTION: Cloning FOXP2, the first gene linked to a hereditary variant of specific language impairment (SLI), has allowed researchers to conduct more precise studies into the nature and developmental path of the molecular bases governing the organisation and functioning of the neuron centres responsible for language processing. DEVELOPMENT: The FOXP2 gene codes for a transcriptional repressor that regulates the proliferation and/or migration of certain neuronal populations in the basal ganglia, cortex, cerebellum and thalamus, and presumably plays a part in the organisation and/or functioning of the fronto-thalamic-striatal system. Moreover, the analysis of the developmental history of the gene suggests that the transcriptional factor FOXP2, although it is quite old, has undergone certain modifications in its secondary structure and has acquired a potential site for phosphorylation for protein kinase C during the recent developmental history of the human species. CONCLUSIONS: The evidence discussed in this article allows us to suggest FOXP2 plays a significant role in the ontogenetic and phylogenetic development of language. On the one hand, it seems to validate certain general models of linguistic processing that call for a more important role of the subcortical structures (above all for the basal ganglia) in that processing. On the other hand, it seems to suggest that the modifications undergone by FOXP2 would have also allowed certain regions (such as Broca's area) to be recruited for language, either by facilitating the appearance of syntax and/or verbal working memory or by transferring control of articulation to those regions, thereby laying down the foundations for the appearance of spoken language.

Brain↗
PubMed2005

Further steps in standardisation. Report of the second annual Proteomics Standards Initiative Spring Workshop (Siena, Italy 17-20th April 2005).

The spring workshop of the HUPO-PSI convened in Siena to further progress the data standards which are already making an impact on data exchange and deposition in the field of proteomics. Separate work groups pushed forward existing XML standards for the exchange of Molecular Interaction data (PSI-MI, MIF) and Mass Spectrometry data (PSI-MS, mzData) whilst significant progress was made on PSI-MS' mzIdent, which will allow the capture of data from analytical tools such as peak list search engines. A new focus for PSI (GPS, gel electrophoresis) was explored; as was the need for a common representation of protein modifications by all workers in the field of proteomics and beyond. All these efforts are contextualised by the work of the General Proteomics Standards workgroup; which in addition to the MIAPE reporting guidelines, is continually evolving an object model (PSI-OM) from which will be derived the general standard XML format for exchanging data between researchers, and for submission to repositories or journals.

Mass Spectrometry↗
PubMed2006

RelEx--relation extraction using dependency parse trees.

MOTIVATION: The discovery of regulatory pathways, signal cascades, metabolic processes or disease models requires knowledge on individual relations like e.g. physical or regulatory interactions between genes and proteins. Most interactions mentioned in the free text of biomedical publications are not yet contained in structured databases. RESULTS: We developed RelEx, an approach for relation extraction from free text. It is based on natural language preprocessing producing dependency parse trees and applying a small number of simple rules to these trees. We applied RelEx on a comprehensive set of one million MEDLINE abstracts dealing with gene and protein relations and extracted approximately 150,000 relations with an estimated performance of both 80% precision and 80% recall. AVAILABILITY: The used natural language preprocessing tools are free for use for academic research. Test sets and relation term lists are available from our website (http://www.bio.ifi.lmu.de/publications/RelEx/).

Algorithms↗
PubMed2022

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Humans↗
PubMed2006

Functional genetic analysis of mutations implicated in a human speech and language disorder.

Mutations in the FOXP2 gene cause a severe communication disorder involving speech deficits (developmental verbal dyspraxia), accompanied by wide-ranging impairments in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. Here we report the first direct functional genetic investigation of missense and nonsense mutations in FOXP2 using human cell-lines, including a well-established neuronal model system. We focused on three unusual FOXP2 coding variants, uniquely identified in cases of verbal dyspraxia, assessing expression, subcellular localization, DNA-binding and transactivation properties. Analysis of the R553H forkhead-box substitution, found in all affected members of a large three-generation family, indicated that it severely affects FOXP2 function, chiefly by disrupting nuclear localization and DNA-binding properties. The R328X truncation mutation, segregating with speech/language disorder in a second family, yields an unstable, predominantly cytoplasmic product that lacks transactivation capacity. A third coding variant (Q17L) observed in a single affected child did not have any detectable functional effect in the present study. In addition, we used the same systems to explore the properties of different isoforms of FOXP2, resulting from alternative splicing in human brain. Notably, one such isoform, FOXP2.10+, contains dimerization domains, but no DNA-binding domain, and displayed increased cytoplasmic localization, coupled with aggresome formation. We hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function.

Alternative Splicing↗
PubMed2005

CAGER: classification analysis of gene expression regulation using multiple information sources.

BACKGROUND: Many classification approaches have been applied to analyzing transcriptional regulation of gene expressions. These methods build models that can explain a gene's expression level from the regulatory elements (features) on its promoter sequence. Different types of features, such as experimentally verified binding motifs, motifs discovered by computer programs, or transcription factor binding data measured with Chromatin Immunoprecipitation (ChIP) assays, have been used towards this goal. Each type of features has been shown successful in modeling gene transcriptional regulation under certain conditions. However, no comparison has been made to evaluate the relative merit of these features. Furthermore, most publicly available classification tools were not designed specifically for modeling transcriptional regulation, and do not allow the user to combine different types of features. RESULTS: In this study, we use a specific classification method, decision trees, to model transcriptional regulation in yeast with features based on predefined motifs, automatically identified motifs, ChlP-chip data, or their combinations. We compare the accuracies and stability of these models, and analyze their capabilities in identifying functionally related genes. Furthermore, we design and implement a user-friendly web server called CAGER (Classification Analysis of Gene Expression Regulation) that integrates several software components for automated analysis of transcriptional regulation using decision trees. Finally, we use CAGER to study the transcriptional regulation of Arabidopsis genes in response to abscisic acid, and report some interesting new results. CONCLUSION: Models built with ChlP-chip data suffer from low accuracies when the condition under which gene expressions are measured is significantly different from the condition under which the ChIP experiment is conducted. Models built with automatically identified motifs can sometimes discover new features, but their modeling accuracies may have been over-estimated in previous studies. Furthermore, models built with automatically identified motifs are not stable with respect to noises. A combination of ChlP-chip data and predefined motifs can substantially improve modeling accuracies, and is effective in identifying true regulons. The CAGER web server, which is freely available at http://cic.cs.wustl.edu/CAGER/, allows the user to select combinations of different feature types for building decision trees, and interact with the models graphically. We believe that it will be a useful tool to facilitate the discovery of gene transcriptional regulatory networks.

Algorithms↗
PubMed2001

Tricross : using dot-plots in sequence-id space to detect uncataloged intergenic features.

MOTIVATION: The process of determining the functional sequence content of an organism is confounded by several factors. Large protein coding sequences are relatively easy to find by statistical methods. Smaller proteins however may escape detection due to their size falling below some arbitrary researcher-defined minimum cutoff, or the inability to precisely define a promoter, or translational start (Delcher et al., Nucleic Acids Res., 27, 4636-4641, 1999). Promoter and regulatory sequences themselves are difficult to define due to a significant amount of allowable sequence variation, as well as a probable lack of any completely accurate whole-organismal gene catalogs to date. Finally, certain genes coding functional RNAs may have insufficient structural or sequence constraints to be detectable by normal sequence structure/pattern searching methods (Eddy and Rivas, Bioinformatics, 16, 583-605, 2000). In those cases where there are multiple closely related organisms that have been sequenced, there is additional information that may be used in the investigation of sequence content-that being the possible conserved nature of functional sequences between the organisms. We present a method for the utilization of this conserved information to detect genes and other potentially functional sequences that may be missed by standard ORF-calling, RNA finding, and pattern matching software. The tricross programs produce a multi-way cross comparison of three sets of sequences, determine which are conserved in all three sets, and produce a graphical (Virtual Reality Modelling Language-VRML; (ISO/IEC 14772-1: 1997, VDC), 1997) representation as well as alignments of all sequence triples found. The software can also be applied to a pair of sequence sets, though the noise in the results increases. RESULTS: Tricross has been used to examine the intergenic-sequence content of the three archaeal Pyrococcus genomes to determine the most highly related sequences remaining between the annotated protein and RNA coding sequences. Set to relatively stringent similarity requirements for the search, tricross found 101 intergenic sequences conserved among the three organisms. Interestingly, 29 of these appear to contain members of a family of small RNA molecules (Kiss-Laszlo et al., EMBO J., 17, 797-807, 1998) only recently discovered in the Archaea (Armbruster, OSU, Diss., 1988; Omer et al., Science, 288, 517-522, 2000; Gaspin et al., J. Mol. Biol., 297, 895-906, 2000). While some of the remaining 72 appear to be individual highly conserved promoter sequences, others have no currently known biological significance. Although originally developed to facilitate the examination of intergenic sequences, none of the tricross logic is inherently specific to intergenic sequences. The software can also be applied to gene sequences, and has been used to produce inter-genomic gene order dot-plots for Haemophilus influenzae (Fleischmann et al., Science, 269, 496-512, 1995) versus H.ducreyi (unpublished data), and Neisseria meningiditis Z2491 (serogroup A) (Parkhill et al., Nature, 404, 502-506, 2000) versus Neisseria meningiditis Z58 (serogroup B) (Tettelin et al., Science, 287, 1809-1815, 2000) versus Neisseria gonorrhoeae (Lewis et al., http://micro-gen.ouhsc.edu/, 2000). AVAILABILITY: The tricross software package is available from http://www.biosci.ohio-state.edu/~ray/bioinformatics/tricross.html. CONTACT: ray@biosci.ohio-state.edu; daniels.7@osu.edu; munsonr@pediatrics.ohio-state.edu SUPPLEMENTARY INFORMATION: Additional data from the cross-genomic comparisons examined in the discussion section are linked from http://www.biosci.ohio-state.edu/~ray/bioinformatics/tricross.html.

Base Sequence↗
PubMed2005

STEPP--Search Tool for Exploration of Petri net Paths: a new tool for Petri net-based path analysis in biochemical networks.

To understand biochemical processes caused by, e. g., mutations or deletions in the genome, the knowledge of possible alternative paths between two arbitrary chemical compounds is of increasing interest for biotechnology, pharmacology, medicine, and drug design. With the steadily increasing amount of data from high-throughput experiments new biochemical networks can be constructed and existing ones can be extended, which results in many large metabolic, signal transduction, and gene regulatory networks. The search for alternative paths within these complex and large networks can provide a huge amount of solutions, which can not be handled manually. Moreover, not all of the alternative paths are generally of interest. Therefore, we have developed and implemented a method, which allows us to define constraints to reduce the set of all structurally possible paths to the truly interesting path set. The paper describes the search algorithm and the constraints definition language. We give examples for path searches using this dedicated special language for a Petri net model of the sucrose-to-starch breakdown in the potato tuber.

Algorithms↗
PubMed2004

Regulatory motif finding by logic regression.

MOTIVATION: Multiple transcription factors coordinately control transcriptional regulation of genes in eukaryotes. Although many computational methods consider the identification of individual transcription factor binding sites (TFBSs), very few focus on the interactions between these sites. We consider finding TFBSs and their context specific interactions using microarray gene expression data. We devise a hybrid approach called LogicMotif composed of a TFBS identification method combined with the new regression methodology logic regression. LogicMotif has two steps: First, potential binding sites are identified from transcription control regions of genes of interest. Various available methods can be used in this step when the genes of interest can be divided into groups such as up-and downregulated. For this step, we also develop a simple univariate regression and extension method MFURE to extract candidate TFBSs from a large number of genes in the availability of microarray gene expression data. MFURE provides an alternative method for this step when partitioning of the genes into disjoint groups is not preferred. This first step aims to identify individual sites within gene groups of interest or sites that are correlated with the gene expression outcome. In the second step, logic regression is used to build a predictive model of outcome of interest (either gene expression or up- and down-regulation) using these potential sites. This 2-fold approach creates a rich diverse set of potential binding sites in the first step and builds regression or classification models in the second step using logic regression that is particularly good at identifying complex interactions. RESULTS: LogicMotif is applied to two publicly available datasets. A genome-wide gene expression data set of Saccharomyces cerevisiae is used for validation. The regression models obtained are interpretable and the biological implications are in agreement with the known resuts. This analysis suggests that LogicMotif provides biologically more reasonable regression models than previous analysis of this dataset with standard linear regression methods. Another dataset of S.cerevisiae illustrates the use of LogicMotif in classification questions by building a model that discriminates between up- and down-regulated genes in iron copper deficiency. LogicMotif identifies an inductive and two repressor motifs in this dataset. The inductive motif matches the binding site of the transcription factor Aft1p that has a key role in regulation of the uptake process. One of the novel repressor sites is highly present in transcription control regions of FeS genes. This site could represent a TFBS for an unknown transcription factor involved in repression of genes encoding FeS proteins in iron deficiency. We establish the robustness of the method to the type of outcome variable used by considering both continuous and binary outcome variables for this dataset. Our results indicate that logic regression used in combination with cluster/group operating binding site identification methods or with our proposed method MFURE is a powerful and flexible alternative to linear regression based motif finding methods. AVAILABILITY: Source code for logic regression is freely available as a package of the R programming language by Ruczinski et al. (2003) and can be downloaded at http://bear.fhcrc.org/~ingor/logic/download/download.html an R package for MFURE is available at http://www.stat.berkeley.edu/~sunduz/software.html

Algorithms↗
PubMed2004

Data-driven computer simulation of human cancer cell.

Using the Diagrammatic Cell Language trade mark, Gene Network Sciences (GNS) has created a network model of interconnected signal transduction pathways and gene expression networks that control human cell proliferation and apoptosis. It includes receptor activation and mitogenic signaling, initiation of cell cycle, and passage of checkpoints and apoptosis. Time-course experiments measuring mRNA abundance and protein activity are conducted on Caco-2 and HCT 116 colon cell lines. These data were used to constrain unknown regulatory interactions and kinetic parameters via sensitivity analysis and parameter optimization methods contained in the DigitalCell computer simulation platform. FACS, RNA knockdown, cell growth, and apoptosis data are also used to constrain the model and to identify unknown pathways, and cross talk between known pathways will also be discussed. Using the cell simulation, GNS tested the efficacy of various drug targets and performed validation experiments to test computer simulation predictions. The simulation is a powerful tool that can in principle incorporate patient-specific data on the DNA, RNA, and protein levels for assessing efficacy of therapeutics in specific patient populations and can greatly impact success of a given therapeutic strategy.

Apoptosis↗
PubMed1989

Computer-assisted evaluation of polydisperse two-dimensional gel patterns of polysaccharide-protein conjugate preparations with regard to size and net charge.

Native Hemophilus influenzae polysaccharide-protein conjugate particles were analyzed by a two-dimensional agarose electrophoresis procedure. In view of their preparation by random chemical crosslinking, the conjugates necessarily exhibit a polydisperse two-dimensional gel pattern which varies depending on the conditions of the particular preparation. The polydisperse patterns were interpreted with regard to the size and surface net charge density of the conjugate on the basis of the extended Ogston model. Data processing was performed by a new program, designated ZWEIDI.DO, written in the language of M-LAB (modeling laboratory). The program computes particle and gel fiber specific parameters from the positions of standards and unknown(s) on the two-dimensional gel using a simultaneous linear least-square curve fitting routine. Based on these calculations, the program serves to compute a nomogram of iso-size and iso-free-mobility profiles. Superimposing these profiles on the gel patterns, the size and free mobility range of the polydisperse conjugate mixtures is obtained. Potentially, the procedure could serve as a tool for quality control in the production of conjugates as vaccines and for the physical characterization of polydisperse subcellular particles and vesicles.

Bacterial Proteins↗
PubMed2003

Cytoskeletal remodeling in lymphocyte activation.

The formerly distinct fields of lymphocyte signal transduction and cytoskeletal remodeling have recently become linked, as proteins involved in transducing signals downstream of lymphocyte antigen receptors have also been implicated in actin cytoskeleton remodeling, microtubule dynamics and regulation of cell polarity. These discoveries have fuelled interest in understanding both the role of the actin cytoskeleton as an integral component of lymphocyte activation and the interplay between lymphoid cell-cell contact sites (immunological synapse), retractile pole structures (uropod, distal pole complex), and Rho-family GTPases (Rac, Rho, Cdc42), their upstream activators (Dbl-family guanine nucleotide exchange factors) and their downstream effectors (WASp, Arp2/3, ADAP). To understand how these complex regulatory networks are wired, a new breed of computational biologists uses mathematical language to reproduce and simulate signaling circuits 'in silico'.

Actin Cytoskeleton↗
PubMed2005

Predicting functional sites with an automated algorithm suitable for heterogeneous datasets.

BACKGROUND: In a previous report (La et al., Proteins, 2005), we have demonstrated that the identification of phylogenetic motifs, protein sequence fragments conserving the overall familial phylogeny, represent a promising approach for sequence/function annotation. Across a structurally and functionally heterogeneous dataset, phylogenetic motifs have been demonstrated to correspond to a wide variety of functional site archetypes, including those defined by surface loops, active site clefts, and less exposed regions. However, in our original demonstration of the technique, phylogenetic motif identification is dependent upon a manually determined similarity threshold, prohibiting large-scale application of the technique. RESULTS: In this report, we present an algorithmic approach that determines thresholds without human subjectivity. The approach relies on significant raw data preprocessing to improve signal detection. Subsequently, Partition Around Medoids Clustering (PAMC) of the similarity scores assesses sequence fragments where functional annotation remains in question. The accuracy of the approach is confirmed through comparisons to our previous (manual) results and structural analyses. Triosephosphate isomerase and arginyl-tRNA synthetase are discussed as exemplar cases. A quantitative functional site prediction assessment algorithm indicates that the phylogenetic motif predictions, which require sequence information only, are nearly as good as those from evolutionary trace methods that do incorporate structure. CONCLUSION: The automated threshold detection algorithm has been incorporated into MINER, our web-based phylogenetic motif identification server. MINER is freely available on the web at http://www.pmap.csupomona.edu/MINER/. Pre-calculated functional site predictions of the COG database and an implementation of the threshold detection algorithm, in the R statistical language, can also be accessed at the website.

Algorithms↗
PubMed1995

Constituting a receptor-ligand information base from quality-enriched data.

Many different resources are needed for analyzing relevant experimental data in drug design. Currently this data is difficult to access, because it is stored in heterogeneous databases, spread over many platforms, poorly interconnected, incomplete, erroneous, or just not electronically available. In order to establish a high quality database for drug design we have developed a new demand-driven methodology for integrating and semantically enriching heterogeneous data from different research areas and for migrating the data into an object-oriented database management system. In this way we have established a database containing well-prepared, relevant data needed for drug design and offering the advantages of modern database technology, like a comprehensive object-oriented data model, a flexible declarative query language and support for persistent storage and sharing of data in a multi-user environment.

Amino Acid Sequence↗
PubMedDate not supplied

A grammatical theory for the conformational changes of simple helix bundles.

Polymers, including biomolecules such as proteins, have two particularly important types of single-molecule transitions: a helix-coil transition, driven by interactions that are local in the chain, and a collapse transition, driven by nonlocal interactions. A long-standing challenge of polymer statistical mechanics has been to deal with both types of transition in a single theoretical framework. The simplest paradigmatic problem would be a theory of helix-bundle folding. Here, we show how the machinery of formal grammars, originally developed in the context of linguistic analysis and programming-language compilation, provides a simple and general way to combine the Zimm-Bragg model of alpha-helices with the model of Chen and Dill for nonlocal interactions in antiparallel polymeric systems. We use a well-known construction in the theory of formal grammars to give the statistical mechanical partition function for two-helix bundles. Predictions are shown to be quite good in comparison to exact enumerations within a lattice model.

Animals↗
PubMed2026

An embedding-based framework enables statistical testing of gene-set function hypotheses inferred by large language models.

Emerging large language models (LLMs) can infer gene functions directly from gene lists, enabling hypothesis generation without predefined gene sets. However, these LLM-derived predictions are qualitative, and principled statistical validation is lacking. Here, we develop an embedding-based statistical framework that transforms gene and function descriptions into vector representations, enabling statistical testing of gene-gene and gene-function relationships and quantitative prioritization of de novo functional hypotheses inferred by LLMs. We benchmark seven state-of-the-art embedding models using curated and retrieval-augmented literature-derived gene descriptions across diverse biological contexts. OpenAI's text-embedding-3-large and Google's gemini-embedding-001 perform best, capturing gene-gene functional relationships in 88.7-92.5% of Gene Ontology biological processes and approximately 98.6% of canonical pathways. In gene-function association analyses, these models achieve high sensitivity (95.2-98.4%) and specificity (72.7-84.3%). Through contamination analysis and evaluation using experimentally informed protein assembly gene sets, our framework distinguishes biologically meaningful LLM-inferred hypotheses from noise, outperforming confidence-based inference and conventional enrichment analysis. We further develop the open-source R package DEGEmbedR and demonstrate its utility for interpreting a drug perturbation-derived differentially expressed gene (DEG) signature lacking significant conventional enrichment results. Together, these results establish LLM-derived embeddings as a quantitative foundation for functional genomics and the statistical validation of LLM-based gene function inference.

Large Language Models↗
PubMed1995

Extraintestinal considerations in inflammatory bowel disease.

If one reviews the literature with zeal, it is increasingly apparent that few organs escape recruitment when IBD is chronic or progressive. Insights into mucosal pathophysiology have helped with understanding the more frequent extraintestinal manifestations, but the mechanisms attendant to the development of less common events (e.g. acute pancreatitis, concurrent gluten sensitive enteropathy, or active pulmonary disease) remain either poorly studied or obscure. It is particularly interesting, however, to read reports of abnormal pulmonary function, generally of the obstructive type, correlated to measurements of abnormal intestinal permeability in patients with either active pulmonary sarcoid or pulmonary involvement in Crohn's disease. It has been further speculated that similarities in the mucosal immune system of the lung and intestine are responsible for evidence of bronchial hyperreactivity in patients with active IBD. Finally, it is important to recognize that extensions of the inflammatory process are not restricted to the development of organ-based events but may be responsible for some of the most frequent systemic abnormalities detected in IBD patients. It is now also well confirmed that the cytokine environment in IBD can support activated coagulation and, in some clinical situations, overt vascular thrombosis. The cerebrovascular complications of IBD are well recognized and range from peripheral venous thrombosis to central stroke syndromes and pseudotumor cerebri. Reports of focal white matter lesions in the brains of patients with IBD or an increased incidence of polyneuropathy may be other clinical examples of regional microvascular clotting. Microvascular injury appears to be more ubiquitously present, with reports ranging from a speculated primary causative role (e.g., granulomatous vasculitis in the mesenteric circulation) to the utility of nailbed vasospasm, in Crohn's disease, as a clinical marker for disease activity. It is also reported that IL-6 suppression of erythropoietin production is a major feature of the chronic anemia seen in active IBD. Moreover, the capacity of peripheral monocytes from active IBD patients to secrete TNF and IL-8 is reported predictive for the degree of therapeutic response from recombinant erythropoietin. These collected observations constitute another excellent example of the symmetry between basic science and clinical utility. It is from the context of applied basic science that many future therapies will arise. Empiricism will lose much of its appeal as clinical observations will be increasingly translated into cellular language. Already in animal models, elemental diets diminish IL-6-related acute inflammatory injury, and reductions in dietary lipid alter the antigenicity of bacteria. Provocatively, in humans, unconfirmed reports have even associated diet therapy with the resolution of uveitis and pyoderma gangrenosum. It is likely that efforts will also be made to induce oral tolerance if specific triggering proteins are discovered or to alter bowel flora if such an arcane area of investigation becomes resurgent.

Anemia↗