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PubMed2026

Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.

Enhancers control tissue-specific gene expression across animals1. Although deep learning2,3 has enabled enhancer prediction and design in mammalian cell lines and non-mammalian model organisms4-10 (reviewed in a previous publication11), it remains unclear whether such approaches can operate within the regulatory complexity of mammalian genomes and tissues in vivo. Here we present a general strategy for designing tissue-specific enhancers that function reliably in mice. We use deep learning to train compact convolutional neural networks on curated chromatin accessibility data and fine-tune them by transfer learning on validated human and mouse enhancers. Guided by these models, we design 15 synthetic enhancers for the heart, limb and central nervous system in mouse embryos, all of which are active in their intended target tissue. These results demonstrate that mammalian enhancer function can be reliably inferred from DNA sequence alone, enabling the predictive de novo design of tissue-specific synthetic enhancers from modest training sets. This work establishes a generalizable framework for programmable control of mammalian gene expression in vivo, opening new avenues in functional genomics, synthetic biology and gene therapy.

Animals↗

PubMed2005

A probabilistic approach to the joint evaluation of firearm evidence and gunshot residues.

The present paper addresses issues that affect both the separate as well as the joint evaluation of firearm evidence (i.e., marks) and gunshot residues (GSR). Mark evidence will be used as a basis to discriminate among barrels through which a bullet in question might have been shot whereas GSR will be used to draw inferences about the distance of firing. Particular attention is drawn to the coherent handling of uncertainties associated with the various parameters considered within each item of evidence. The proposed analysis relies on a probabilistic viewpoint that uses graphical models (i.e., Bayesian networks) as an aid to cope with the complexity induced by the number of variables considered. The paper discusses how an approach based on a probabilistic network environment can be used for the formal analysis and construction of arguments. Emphasis is made on the gain of insight into structural dependencies that may be uncovered when the evaluative process is extended beyond single items of scientific evidence.

Bayes Theorem↗

PubMed2004

Hypervariable plastid locus variation and intron evolution in the Anacamptis palustris lineage.

Data on the organization of a hypervariable chloroplast locus in the Anacamptis palustris (Orchidaceae) lineage are provided and used to infer the pattern of molecular evolution in this group. A large survey of sequence variation in A. palustris and allied taxa reveals several repeat types differing in number and organization that occur in the same plastid region. The resulting repeat type network suggests that at least seven different minisatellite loci evolved near each other in the tRNALEU intron and indicates the presence of at least three main phyletic lines in the A. palustris lineage.

Base Sequence↗

PubMed2005

A neural strategy for the inference of SH3 domain-peptide interaction specificity.

BACKGROUND: The SH3 domain family is one of the most representative and widely studied cases of so-called Peptide Recognition Modules (PRM). The polyproline II motif PxxP that generally characterizes its ligands does not reflect the complex interaction spectrum of the over 1500 different SH3 domains, and the requirement of a more refined knowledge of their specificity implies the setting up of appropriate experimental and theoretical strategies. Due to the limitations of the current technology for peptide synthesis, several experimental high-throughput approaches have been devised to elucidate protein-protein interaction mechanisms. Such approaches can rely on and take advantage of computational techniques, such as regular expressions or position specific scoring matrices (PSSMs) to pre-process entire proteomes in the search for putative SH3 targets. In this regard, a reliable inference methodology to be used for reducing the sequence space of putative binding peptides represents a valuable support for molecular and cellular biologists. RESULTS: Using as benchmark the peptide sequences obtained from in vitro binding experiments, we set up a neural network model that performs better than PSSM in the detection of SH3 domain interactors. In particular our model is more precise in its predictions, even if its performance can vary among different SH3 domains and is strongly dependent on the number of binding peptides in the benchmark. CONCLUSION: We show that a neural network can be more effective than standard methods in SH3 domain specificity detection. Neural classifiers identify general SH3 domain binders and domain-specific interactors from a PxxP peptide population, provided that there are a sufficient proportion of true positives in the training sets. This capability can also improve peptide selection for library definition in array experiments. Further advances can be achieved, including properly encoded domain sequences and structural information as input for a global neural network.

Amino Acid Motifs↗

PubMed1987

Myogenesis in vitro as seen with the scanning electron microscope.

In this paper, we review our recent observations by scanning electron microscopy (SEM) on the differentiation of the cell surface and cytoplasmic organelles in embryonic chick skeletal muscle cells in vitro. The changes of the surface structures of myoblasts during mitosis were essentially similar to those of other cell types, but the characteristic spindle shape of myoblasts did not change throughout most of this period. Cytoskeletal structures under the sarcolemma were examined by Triton extraction and metal coating. Cells in S, G2 and M possessed a dense, and those in G1 a loose filament network under the membrane. Myotubes possessed a dense network under the sarcolemma. In the fusion area between a myoblast and a myotube, the cytoskeletal domain of the former could be distinguished from the latter because of the mosaic appearance of the subsarcolemmal cytoskeletal network. This network was composed predominantly of 10-13 nm filaments; they were identified as actin filaments because of their decoration with myosin subfragment-1. Triton treatment and thiocarbohydrazide-osmium staining allowed us to visualize myofibrils. They ran in the direction of inferred stress lines brought about by elongation and adhesion of the cells to substrate. Intracellular membranous organelles could be seen by the freeze-polishing and osmium-maceration procedure. Mitochondria exhibited complex irregular branchings. T system tubules ran a tortuous course. Sarcoplasmic reticula with occasional dilatations were connected to each other. The results are of sufficient promise to encourage more extensive analysis of myogenesis by SEM.

Animals↗

PubMed2002

N400 and automatic semantic processing abnormalities in patients with schizophrenia.

BACKGROUND: One factor hypothesized to underlie thinking disturbance in patients with schizophrenia is abnormal or disinhibited automatic spreading activation of semantic networks, which can be assessed using the N400 event-related potential. N400 is a negative-going component elicited at about 400 milliseconds following semantic stimuli that are not primed by the preceding context. Semantic priming refers to facilitated semantic processing gained through preexposure to semantic context, which can happen automatically or strategically. Using N400, inferences can be drawn regarding the extent to which a given context primes a word. METHODS: During a picture-word matching task, N400s to primed (exact match) and unprimed (remotely related) words were recorded from 18 healthy control subjects and 18 patients with schizophrenia performing a picture-word matching task. A short interval (325 milliseconds) between picture and word onset (stimulus-onset asynchrony) was used to optimize the role of automatic spreading semantic activation and to minimize the role of attention, expectancy, preparation, and working memory. RESULTS: Despite behavioral evidence of normal semantic priming, patients generated an abnormally small N400 (ie, less negative) to unprimed words. The N400 to primed words was neither larger nor smaller in patients than in controls, suggesting normal use of context. CONCLUSIONS: A reduced N400 to unprimed words in patients with schizophrenia suggests that there was inappropriate priming of words by remotely related semantic contexts. This is consistent with an overly broad automatic spread of activation through semantic networks in patients with schizophrenia.

Adult↗

PubMed2006

Population structure inferred by local spatial autocorrelation: an example from an Amerindian tribal population.

Spatial autocorrelation (SA) methods were recently extended to detect local spatial autocorrelation (LSA) at individual localities. LSA statistics serve as useful indicators of local genetic population structure. We applied this method to 15 allele frequencies from 43 villages of a South American tribe, the Yanomama. Based on a network of links <or=51 km between neighboring villages, we calculated LSA statistics for Moran, Geary, and Getis-Ord coefficients. We also developed two new, rescaled indices of local SA. Local indicators of positive SA highlight villages surrounded by genetically similar near neighbors. Negative LSA statistics indicate sharp genetic differences from near neighbors. Markedly positive LSA was found for all 11 outlier villages. The most negatively LSA villages are in the central, densely connected cluster. The Getis-Ord coefficients of suitably transformed allele frequencies point to clusters of villages with unusually high or low allelic polymorphisms. The most homozygous villages are all in the four geographically isolated village clusters. The most polymorphic villages are all in the large, densely settled Yanomame dialect group. An ad hoc linguistic isolation index between neighboring villages showed that villages in isolated pairs and triplets have linguistically similar neighbors, whereas nine villages with notably negative LSA are all near dialect and kinship boundaries. The location of a village with respect to the graph structure of its neighborhood affects its LSA and genetic polymorphism. The implications of these findings for the population structure of the Yanomama are compatible with those from an earlier study of global SA in these villages.

Demography↗

PubMed2005

The leaf size-twig size spectrum of temperate woody species along an altitudinal gradient: an invariant allometric scaling relationship.

BACKGROUND AND AIMS: The leaf size-twig size spectrum is one of the leading dimensions of plant ecological variation, and now it is under development. The purpose of this study was to test whether the relationship between leaf size and twig size is isometric or allometric, and to examine the relationship between plant allometric growth and life history strategies in the spectrum. METHODS: Leaf and stem characters-including leaf and stem mass, total leaf area, individual leaf area, stem cross-sectional area, leaf number and stem length-at the twig level for 59 woody species were investigated along an altitudinal gradient on Changbaishan Mountain in the temperate zone of China. The environmental gradient ranges from temperate broad-leaved mixed forest at low altitude, to conifer forest at middle altitude, and to sub-alpine birch forest at high altitude. The scaling relationships between stem cross-sectional area and stem mass, stem mass and leaf mass, and leaf mass and leaf area at the twig level were simultaneously determined. KEY RESULTS: Twig cross-sectional area was found to have invariant allometric scaling relationships with the stem mass, leaf mass, total leaf area and individual leaf area, all with common slopes being significantly larger than 1, for three altitudinal-zoned vegetation types under investigation. However, leaf mass was found to be isometrically related to stem mass and leaf area along the environmental gradient. Based on the predictions of previous models, the exponent value of the relationship between twig cross-sectional area and total leaf area can be inferred to be 1.5, which falls between the confidence intervals of the relationship at each altitude, and between the confidence intervals of the common slope value (1.17-1.56) of this study. This invariant scaling relationship is assumed to result from the fractural network and/or developmental constraints of plants. The allometric constants (y-intercepts) of the relationships between the stem cross-sectional area and leaf area (both total leaf area and individual leaf area) were found to decrease significantly along the altitudinal gradient. This suggests that the species would support less leaf area at a given twig cross-sectional area with increasing environmental stress. CONCLUSIONS: This study demonstrated that plants respond to the environmental gradient by changing the y-intercepts of the relationship between leaf size-twig size, while keeping the exponent value of the allometric relationship as an invariant constant. The allometric growth in the twig size-leaf size spectrum is related to many other components of plant life history strategy, including the well established life history trade-off between efficiency and safety in the hydraulic transport of water.

Acclimatization↗

PubMed1998

RNA editing in the free-living bodonid Bodo saltans.

In parasitic kinetoplastid protozoa, mitochondrial (mt) mRNAs are post-transcriptionally edited by insertion and deletion of uridylate residues, the information being provided by guide (g) RNAs. In order to further explore the role and evolutionary history of this process, we searched for editing in mt RNAs of the free-living bodonid Bodo saltans. We found extensive editing in the transcript for NADH dehydrogenase (ND) subunit 5, which is unedited in trypanosomatids. In contrast, B.saltans cytochrome c oxidase (cox) subunit 2 and maxicircle unidentified reading frame (MURF) 2 RNAs display limited editing in the same regions as their trypanosomatid counterparts. A putative intramolecular cox2 gRNA and the gene for gMURF2-I directing the insertion of only one U in the 5' editing domain of MURF2 RNA, are conserved in B.saltans. This lends (further) evolutionary support to the proposed role of these sequences as gRNAs. Phylogenetic analysis showed that B.saltans is more closely related to trypanosomatids than the cryptobiids Trypanoplasma borreli and Cryptobia helicis, in line with the trypanosomatid-like cox2 and MURF2 RNA editing patterns. Nevertheless, other features like the apparent absence of a catenated mtDNA network, are shared with bodonid and cryptobiid species. ND5 RNA editing may represent yet another example of editing 'on the way out' during kinetoplastid evolution, but in view of the fact that cox2 RNA is unedited in T. borreli and C.helicis, we infer that the editing of this RNA may have arisen relatively recently. Our results provide the first examples of RNA editing in a free-living kinetoplastid, indicating that there is no direct link between U-insertion/deletion editing and a parasitic lifestyle.

Amino Acid Sequence↗

PubMed2006

Enabling a powerful marine and offshore decision-support solution through Bayesian network technique.

A powerful practical solution is by far the most desired output when making decisions under the realm of uncertainty on any safety-critical marine or offshore units and their systems. With data and information typically being obtained incrementally, adopting Bayesian network (BN) is shown to realistically deal with the random uncertainties while at the same time making risk assessments easier to build and to check. A well-matched methodology is proposed to formalize the reasoning in which the focal mechanism of inference processing relies on the sound Bayes's rule/theorem that permits the logic. Expanding one or more influencing nodal parameters with decision and utility node(s) also yields an influence diagram (ID). BN and ID feasibility is shown in a marine evacuation scenario and that of authorized vessels to floating, production, storage, and offloading collision, developed via a commercial computer tool. Sensitivity analysis and validation of the produced results are also presented.

Accidents, Occupational↗

PubMed1995

Spatial distribution of connexin43, the major cardiac gap junction protein, visualizes the cellular network for impulse propagation from sinoatrial node to atrium.

Myocytes are electrically coupled by gap junctions, which are composed of low-resistance intercellular channels. The major cardiac gap junction protein is connexin43 (Cx43). The distribution of Cx43 has been studied by immunofluorescence to visualize the electrical coupling between atrial tissue and sinoatrial node. From modeling studies, this coupling was inferred to be gradual in order to shield the sinoatrial node from the atrial hyperpolarizing influence. The actual Cx43 labeling pattern did not show the expected gradient but instead a rather black and white staining in a striking pattern of strands of cells. We used an immunohistochemical marker (anti-alpha-smooth muscle actin [alpha SMA]) that specifically cross-reacts with guinea pig sinoatrial node cells together with Cx43 antibody to stain previously electrophysiologically mapped sinoatrial nodes. We found that in the guinea pig sinoatrial node the impulse originates in an alpha SMA-positive, virtually Cx43-negative, region (primary pacemaker region). The impulse then travels obliquely upward to the crista terminalis through a region where layers of alpha SMA-positive cells alternate with layers of Cx43-positive SMA-negative cells. The layers of Cx43-positive cells appear to become broader and thicker in the direction of the crista terminalis, whereas the layers of alpha SMA-positive cells become thinner and narrower. Lateral contacts between Cx43- and alpha SMA-positive cells were very sparse and only detected where the Cx43-positive strands ended (the region where alpha SMA-positive cells fill the whole space between endocardium and epicardium, ie, the putative primary pacemaker region). From these results, we conclude that the primary pacemaker is shielded from the hyperpolarizing influence of the atrium by a gradient in coupling brought about by tissue geometric factors rather than by a gradient of gap junction density.

Actins↗

PubMed2006

Exploring dynamics of protein structure determination and homology-based prediction to estimate the number of superfamilies and folds.

BACKGROUND: As tertiary structure is currently available only for a fraction of known protein families, it is important to assess what parts of sequence space have been structurally characterized. We consider protein domains whose structure can be predicted by sequence similarity to proteins with solved structure and address the following questions. Do these domains represent an unbiased random sample of all sequence families? Do targets solved by structural genomic initiatives (SGI) provide such a sample? What are approximate total numbers of structure-based superfamilies and folds among soluble globular domains? RESULTS: To make these assessments, we combine two approaches: (i) sequence analysis and homology-based structure prediction for proteins from complete genomes; and (ii) monitoring dynamics of the assigned structure set in time, with the accumulation of experimentally solved structures. In the Clusters of Orthologous Groups (COG) database, we map the growing population of structurally characterized domain families onto the network of sequence-based connections between domains. This mapping reveals a systematic bias suggesting that target families for structure determination tend to be located in highly populated areas of sequence space. In contrast, the subset of domains whose structure is initially inferred by SGI is similar to a random sample from the whole population. To accommodate for the observed bias, we propose a new non-parametric approach to the estimation of the total numbers of structural superfamilies and folds, which does not rely on a specific model of the sampling process. Based on dynamics of robust distribution-based parameters in the growing set of structure predictions, we estimate the total numbers of superfamilies and folds among soluble globular proteins in the COG database. CONCLUSION: The set of currently solved protein structures allows for structure prediction in approximately a third of sequence-based domain families. The choice of targets for structure determination is biased towards domains with many sequence-based homologs. The growing SGI output in the future should further contribute to the reduction of this bias. The total number of structural superfamilies and folds in the COG database are estimated as approximately 4000 and approximately 1700. These numbers are respectively four and three times higher than the numbers of superfamilies and folds that can currently be assigned to COG proteins.

Data Interpretation, Statistical↗

PubMed1989

[Psychiatric long-term hospitalization--and how does life go on?].

Problems of longterm psychiatric hospitalisation are represented at the example of the topical supply situation in the mental hospital Bezirksnervenklinik Haldensleben. By means of a shown catalogue of symptoms from longterm psychiatric hospitalised patients tasks of care and inferences are discussed under the aspect, that the living and therapy conditions respectively their structures of the psychical sick persons authenticately show reactions on the course of illness and attendance. A lot of graduated care-offers in form of a therapeutical network first of all open a social reintegration in regard of individual and reality. At the same time hence it follows the chance for modifications in the psychiatric hospital.

Deinstitutionalization↗

PubMed2003

Better prediction of sub-cellular localization by combining evolutionary and structural information.

The native sub-cellular compartment of a protein is one aspect of its function. Thus, predicting localization is an important step toward predicting function. Short zip code-like sequence fragments regulate some of the shuttling between compartments. Cataloguing and predicting such motifs is the most accurate means of determining localization in silico. However, only few motifs are currently known, and not all the trafficking appears regulated in this way. The amino acid composition of a protein correlates with its localization. All general prediction methods employed this observation. Here, we explored the evolutionary information contained in multiple alignments and aspects of protein structure to predict localization in absence of homology and targeting motifs. Our final system combined statistical rules and a variety of neural networks to achieve an overall four-state accuracy above 65%, a significant improvement over systems using only composition. The system was at its best for extra-cellular and nuclear proteins; it was significantly less accurate than TargetP for mitochondrial proteins. Interestingly, all methods that were developed on SWISS-PROT sequences failed grossly when fed with sequences from proteins of known structures taken from PDB. We therefore developed two separate systems: one for proteins of known structure and one for proteins of unknown structure. Finally, we applied the PDB-based system along with homology-based inferences and automatic text analysis to annotate all eukaryotic proteins in the PDB (http://cubic.bioc.columbia.edu/db/LOC3D). We imagine that this pilot method-certainly in combination with similar tools-may be valuable target selection in structural genomics.

Algorithms↗

PubMed2004

Inferring false beliefs from the actions of oneself and others: an fMRI study.

The ability to make judgments about mental states is critical to social interactions. Simulation theory suggests that the observer covertly mimics the activity of the observed person, leading to shared states of mind between the observer and the person observed. We tested this hypothesis by investigating the neural networks activated while subjects watched videos of themselves and of others lifting a box, and judged the beliefs of the actors about the weight of the box. A parietal premotor circuit was recruited during action perception, and the activity started earlier when making judgments about one's own actions as opposed to those of others. This earlier activity in action-related structures can be explained by simulation theory on the basis that when one observes one's own actions, there is a closer match between the simulated and perceived action than there is when one observes the actions of others. When the observers judged the actions to reflect a false belief, there was activation in the superior temporal sulcus, orbitofrontal, paracingulate cortex and cerebellum. We suggest that this reflects a mismatch between the perceived action and the predicted action's outcomes derived from simulation.

Brain Mapping↗

PubMed2006

Large-scale prediction of disulphide bridges using kernel methods, two-dimensional recursive neural networks, and weighted graph matching.

The formation of disulphide bridges between cysteines plays an important role in protein folding, structure, function, and evolution. Here, we develop new methods for predicting disulphide bridges in proteins. We first build a large curated data set of proteins containing disulphide bridges to extract relevant statistics. We then use kernel methods to predict whether a given protein chain contains intrachain disulphide bridges or not, and recursive neural networks to predict the bonding probabilities of each pair of cysteines in the chain. These probabilities in turn lead to an accurate estimation of the total number of disulphide bridges and to a weighted graph matching problem that can be addressed efficiently to infer the global disulphide bridge connectivity pattern. This approach can be applied both in situations where the bonded state of each cysteine is known, or in ab initio mode where the state is unknown. Furthermore, it can easily cope with chains containing an arbitrary number of disulphide bridges, overcoming one of the major limitations of previous approaches. It can classify individual cysteine residues as bonded or nonbonded with 87% specificity and 89% sensitivity. The estimate for the total number of bridges in each chain is correct 71% of the times, and within one from the true value over 94% of the times. The prediction of the overall disulphide connectivity pattern is exact in about 51% of the chains. In addition to using profiles in the input to leverage evolutionary information, including true (but not predicted) secondary structure and solvent accessibility information yields small but noticeable improvements. Finally, once the system is trained, predictions can be computed rapidly on a proteomic or protein-engineering scale. The disulphide bridge prediction server (DIpro), software, and datasets are available through www.igb.uci.edu/servers/psss.html.

Amino Acid Sequence↗

PubMed1980

High molecular weight protein MAP 2 promoting microtubule assembly in vitro is associated with microtubules in cells.

Brain high molecular weight (HMW) protein promoting microtubule assembly in vitro and identical to MAP 2 (one of the proteins which copurify with tubulin through microtubule assembly-disassembly cycles), is shown to be associated with microtubules in interphase and mitotic cells. This HMW protein was purified earlier (Kuznetsov et al., 1978), directly from bovine brain without previous obtaining total microtubule protein. Now we have obtained a monospecific antibody against it. Identity of the HMW protein with MAP 2 is inferred from SDS-electrophoresis and immunological tests; its intracellular localization is determined by indirect immunofluorescent staining of cultured bovine tracheal epithelium. the anti-MAP 2 antibody stains the same structures in the cells as the tubulin antibody: it stains the fibrillar network in interphase cells, mitotic spindle, and the stem body. No fibrillar structures in the cells treated with colchicine or vinblastine were stained with the antibody against MAP 2. Anti-MAP 2 also stains tubulin-containing paracrystals which have been formed in the vinblastine-treated cells. Therefore HMW protein MAP 2 which promotes tubulin polymerization in vitro is associated with microtubules in vivo.

Animals↗

PubMed2002

Receptor modeling application framework for particle source apportionment.

Receptor models infer contributions from particulate matter (PM) source types using multivariate measurements of particle chemical and physical properties. Receptor models complement source models that estimate concentrations from emissions inventories and transport meteorology. Enrichment factor, chemical mass balance, multiple linear regression, eigenvector. edge detection, neural network, aerosol evolution, and aerosol equilibrium models have all been used to solve particulate air quality problems, and more than 500 citations of their theory and application document these uses. While elements, ions, and carbons were often used to apportion TSP, PM10, and PM2.5 among many source types, many of these components have been reduced in source emissions such that more complex measurements of carbon fractions, specific organic compounds, single particle characteristics, and isotopic abundances now need to be measured in source and receptor samples. Compliance monitoring networks are not usually designed to obtain data for the observables, locations, and time periods that allow receptor models to be applied. Measurements from existing networks can be used to form conceptual models that allow the needed monitoring network to be optimized. The framework for using receptor models to solve air quality problems consists of: (1) formulating a conceptual model; (2) identifying potential sources; (3) characterizing source emissions; (4) obtaining and analyzing ambient PM samples for major components and source markers; (5) confirming source types with multivariate receptor models; (6) quantifying source contributions with the chemical mass balance; (7) estimating profile changes and the limiting precursor gases for secondary aerosols; and (8) reconciling receptor modeling results with source models, emissions inventories, and receptor data analyses.

Air Pollutants↗