Transformation processes upon the visual code.
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Drosophila melanogaster has long been at the forefront of studies of transcriptional regulation in animals. Many fundamental ideas--such as cis control elements that act over long distances, the regulation of development by hierarchical cascades of transcription factors, dosage compensation, and position effect variegation--originated from studies of the fruit fly. The recent completion of the euchromatic DNA sequence of Drosophila is another breakthrough. The sequence data highlight important unanswered questions. For example, only one-fifth of the 124 Mb of Drosophila euchromatic DNA codes for protein. The function of the remaining 100 Mb of mostly unique DNA is largely unknown. Some proportion of this non-reading frame DNA must encode the functional recognition sites targeted by the approximately 700 sequence-specific DNA binding proteins that regulate transcription in Drosophila, but what proportion? Most or very little? Promoter sequences by definition contain all of the cis information that specifies how gene transcription is regulated. However, it has been difficult to decipher this information and predict the patterns of RNA expression. How do we break this "transcriptional code"? Mechanistic studies, using simple model promoters, indicate that transcription is controlled by the coordinate action of sequence-specific DNA binding proteins interacting with the general transcriptional machinery via intermediary adapters and chromatin remodeling activities. How can we integrate this biochemical information with data from genome-wide studies to describe the generation of highly complex patterns of transcription? Here, we discuss recent studies that may point the way ahead. We also highlight difficulties that the field faces in dissecting transcriptional control in the post-genome era.
The concepts of molecular similarity and molecular complementarity, playing important roles in the broad field of molecular recognition, are chemical problems, in which the eyeball technique used by a human observer is very successful but which are very hard to code into a computer algorithm. Based on the model of molecular surfaces, our new approach defines overlapping surface patches with similar molecular properties. These patches are used to represent local features of the molecule in a way, which is beyond the atomistic resolution but can nevertheless be applied in partial similarity as well as complementarity analyses in a very general sense. It is shown that this molecular description can be used as the first step in a docking algorithm for complexes, where the structures of both molecules are known, as well as for the identification of possible active sites without the knowledge of specific molecules binding to this site.
We examined memory for pictures and words in adults with mental retardation and a control group of adults of normal intelligence. During acquisition, sets of simple line drawings and matching words were presented for study using an intentional learning procedure. The principle dependent measures were free recall and recognition. Measures of working memory span were also administered. Pictorial superiority effects occurred in free recall and recognition for both intelligence-level groups. Correlational analyses indicated that working memory span was primarily related to recall performance, irrespective of stimulus format. These data strongly suggest that persons with mental retardation can utilize nonverbal memory codes to support long-term retention as effectively as do adults of normal intelligence.
This article presents a brain-damaged patient (RR) suffering from cognitive deficits following neurological insults, who showed a selective impairment in number transcoding. Except for written verbal numeral to arabic transcoding, his ability to transcode numerals, including writing arabic numerals to dictation, is largely preserved. Other number processing skills, including numeral recognition, numeral comprehension, and calculation, were unimpaired. Semantic and asemantic models of number processing cannot easily account for the patient's performance and it is suggested that the number transcoding system should include different code-dependent pathways for arabic transcoding from spoken verbal numerals and from written verbal numerals. Since the errors produced in the impaired transcoding rely upon the syntactical structure of numeral stimuli, it is also proposed that transcoding code-dependent pathways should reflect the structure of the verbal numeral system, especially the difference between sum and product relationships.
1. The inferotemporal cortex (IT) has been thought to play an essential and specific role in visual object discrimination and recognition, because a lesion of IT in the monkey results in a specific deficit in learning tasks that require these visual functions. To understand the cellular basis of the object discrimination and recognition processes in IT, we determined the optimal stimulus of individual IT cells in anesthetized, immobilized monkeys. 2. In the posterior one-third or one-fourth of IT, most cells could be activated maximally by bars or disks just by adjusting the size, orientation, or color of the stimulus. 3. In the remaining anterior two-thirds or three-quarters of IT, most cells required more complex features for their maximal activation. 4. The critical feature for the activation of individual anterior IT cells varied from cell to cell: a complex shape in some cells and a combination of texture or color with contour-shape in other cells. 5. Cells that showed different types of complexity for the critical feature were intermingled throughout anterior IT, whereas cells recorded in single penetrations showed critical features that were related in some respects. 6. Generally speaking, the critical features of anterior IT cells were moderately complex and can be thought of as partial features common to images of several different natural objects. The selectivity to the optimal stimulus was rather sharp, although not absolute. We thus propose that, in anterior IT, images of objects are coded by combinations of active cells, each of which represents the presence of a particular partial feature in the image.
The ethical statements which have historically been subscribed to by the dental profession have had the benefit of the patient as their primary goal. Recognition of this goal, and of the education and training of a dentist, has resulted in society affording to the profession the privilege and obligation of self-government. The Association calls upon members of the profession to be caring and fair in their contact with patients. Although the structure of society may change, the overriding obligation of the dentist will always remain the duty to provide quality care in a competent and timely manner. All members must protect and preserve the high standards of oral health care provided to the public by the profession. They must strive to improve the care delivered--through education, training, research and, most of all, adherence to a stringent code of ethics, structured to meet the needs of the patient.
The application of automatic approaches in EEG pattern recognition essentially has two aims: to increase the level of objectivity (by means of quantification) and to decrease the amount of diagnostic work (by means of data reduction). In this study a computerized spike-wave detection method is described, realized on a small laboratory computer (PDP 11/03) and especially designed for the analysis of long term registrations. The program is written in FORTRAN in order to provide a high level of flexibility. The user may easily modify it for his own purposes. Pattern recognition is based on the configuration of maxima and minima. Different degrees of digital filtering is used for spike analysis and wave analysis. The time codes of the events are registered and stored on magnetic disk. In a subsequent computer run the results may graphically be displayed or submitted to further analysis. An example is given testing in which way the results depend on the choice of the parameter set (duration and amplitude of spike and wave). The time course of the frequency of SW-events (or regular SW-sequences, respectively) are compared to the results of conventional analysis.
The nucleotide sequence of the cytochrome oxidase subunit 2 (cox2) and val-tRNA genes and surrounding regions from Kluyveromyces lactis mitochondrial DNA is reported. Analysis of the coding region shows that the codons CUN (Thr), CGN (Arg) and AUA (Met) are absent in this gene. A single sequence, ATATAAGTAA, identical to the baker's yeast mtRNA polymerase recognition site, was detected upstream of val-tRNA. This sequence is absent from regions between val-tRNA-cox2 and cox2-cox1. In addition a sequence AATAATATTCTT, identical to the mRNA processing site in other yeast mitochondrial genomes is present 32-43 bp downstream to the TAA stop codon for the cox2 gene. Another short conserved sequence of 5 bp, TCTAA, is present upstream of the coding regions of cox2 genes in several yeasts, including K. lactis, but is not present upstream of other genes. Comparison of cox2 sequences from other organisms indicates that the mitochondrial DNA of K. lactis is closely related to that of Saccharomyces cerevisiae.
This study investigated the effects of left and right intracranial tumors on picture and word recognition memory. We hypothesized that left hemispheric (LH) patients would exhibit greater word recognition memory impairment than right hemispheric (RH) patients, with no significant hemispheric group picture recognition memory differences. The LH patient group obtained a significantly slower mean picture recognition reaction time than the RH group. The LH group had a higher proportion of tumors extending into the temporal lobes, possibly accounting for their greater pictorial processing impairments. Dual coding and enhanced visual imagery may have contributed to the patient groups' similar performance on the remainder of the measures.
Short tail fibres of T-even like phages are involved in host recognition. To determine the specificity of the fibres, the region containing gene 12 of phages T2, K3, and K3hx was cloned. The genes 11, 12, wac, and 13, coding for the baseplate outer wedge, short tail fibres, collar wishes, and a head completion component, respectively, were localized on the cloned fragments. Plasmid-encoded gene 12 could be expressed without helper phage. Efficient expression of gene 12 from T2 and K3hx made an extraction of protein 12 possible. Hybrid phages obtained by in vitro complementation, recombination analysis and protein 12 binding to host range mutant bacteria excluded a role of the short tail fibres from T2, K3 or K3hx in the recognition of outer membrane proteins. Binding patterns of protein 12 to different Escherichia coli lipopolysaccharide mutants and inhibition of binding of protein 12 by a monoclonal antibody against the core region of E. coli K12 lipopolysaccharide suggested that heptose residues are necessary for efficient binding. The binding site of the same monoclonal antibody is different from the short tail fibre binding site in an E. coli B strain suggesting different binding specificities of protein 12. Thus, the ability of different bacterial strains to inactivate phage could be related to differences in the binding specificity of the short tail fibres for the lipopolysaccharides of these bacteria.
BMCP18(2) is one of the major cuticle proteins identified in the larval cuticle of the silkworm, Bombyx mori. A genomic clone coding for BMCP18 was isolated from a B. mori genomic library, and its structure was analyzed. The BMCP18 gene consists of three exons interspersed by two introns. Bm1 element-like sequences were identified around this gene, suggesting possible involvement of this retroposon in the duplication of B. mori cuticle protein genes during evolution. A structural comparison of the BMCP18 gene and related cuticle protein genes of other lepidopteran species (MSCP14.6 and HCCP12) showed that the 5' upstream region of the BMCP18, MSCP14.6, and HCCP12 genes has a 12-bp identical sequence matching the recognition sequence for transcription factors COUP-TF and HNF-4. This implies that molecular mechanisms regulating expression of these cuticle protein genes are also conserved. mRNAs coding for Bmsvp, the B. mori homolog of Drosophila Seven-up, which is known as a homolog of vertebrate COUP-TF, and BmHNF-4, a homolog of vertebrate HNF-4, were detected in the larval epidermis. Bmsvp bound to the 12-bp sequence in vitro, suggesting that Bmsvp regulates the BMCP18 gene expression.
In mice as well as humans, cytotoxic T lymphocytes (CTL) specific for wild-type-sequence (wt) p53 peptides have been shown to react against a wide range of tumors, but not normal cells. As such, they are attractive candidates for developing broadly applicable cancer vaccines. Of particular interest is the potential of using p53-based vaccines in high-risk individuals to prevent cancer. Methylcholanthrene, an immunosuppressive polycyclic hydrocarbon carcinogen implicated as a causative agent in human cancers, has long been used to induce murine tumors with a high incidence of genetic alterations and sensitivity to wt p53-specific CTL. To analyze the potential of p53-based vaccines on primary tumors, we evaluated the efficacy of DNA and dendritic cell vaccines targeting wt p53 peptides given to methylcholanthrene-treated mice in the protection or therapy settings. The results indicate that the efficacy of these vaccines relative to reducing tumor incidence were severely compromised by vaccine-induced tumor escape. As compared to tumors induced in non-immunized mice, a higher incidence of epitope-loss tumors was detected in tumors from the immunized mice. The increase in tumor escape arose as a consequence of either increased frequencies of mutations within/flanking p53 epitope-coding regions or downregulation of expression of the major histocompatibility complex Class I molecules that present these epitopes for T cell recognition These findings are consistent with current views of immunoselection occurring in patients receiving tumor peptide-based immunotherapy, and impact on the design and implementation of p53-based vaccines, in particular, those aimed at treating individuals at high risk for developing cancer.
The relationship between molecular structure and duration of depressant effect for barbiturates was investigated. A data set of 160 5,5'-disubstituted barbiturates with various acyclic substituents was coded using 47 numerical descriptors including fragments, substructures, environmental descriptors, and molecular connectivity indexes. All descriptors were derived directly from the connection tables of the barbiturates. Using an interactive error-correction feedback algorithm, linear discriminant functions were developed that could dichotomize the data set with respect to several thresholds separating longer from shorter acting compounds. Feature selection was used to focus on the relatively few structural descriptors sufficient to support linear separability. For three specific thresholds, nine, 11, and nine descriptors were sufficient. The importance of these descriptors and the utility of the technique are discussed. Predictive abilities of approximately 94% were obtained for known barbiturates of the same general molecular types.
The transfer of lipids in aqueous environments such as serum has been attributed to a recently characterized class of proteins. Abnormal regulation of serum lipids by these proteins is thought to be a key event in the pathophysiology of cardiovascular diseases. Lipopolysaccharide (endotoxin) binding protein (LBP) was identified by virtue of its ability to bind bacterial lipid A. We have analyzed the exon-intron organization of the LBP gene and the nucleotide sequence of its approximately 20 kb spanning 5'- and 3'-untranslated regions. When comparing the genomic organization of LBP with that of two other genes coding for lipid transfer proteins, significant homologies were found. The LBP gene includes 15 exons, and the 2-kb promoter contains recognition elements of acute phase-typical reactants and a repetitive 12-mer motif with an as yet unknown protein-binding property. Detailed sequence comparison revealed a closer relatedness of LBP with PLTP than with CETP as demonstrated by an almost identical intron positioning. This high degree of similarity supports functional studies by others suggesting that like LBP, PLTP may also be able to bind and transport bacterial lipopolysaccharide.
This study examined individual differences in children's emotional understanding and behavioral adjustment. Participants included 220 first- and second-grade children (75% regular education, 25% special education) who were individually interviewed using the Kusche Affective Interview--Revised. Dependent measures of emotional understanding and experience included the ability to provide personal examples of 10 different emotions and the cues used for recognition of five emotions in oneself and other persons. Children were also administered the WISC-R Vocabulary, Block Design, and Coding subtests. One parent independently completed an Achenbach Child Behavior Checklist for each child. Results indicated that children who were rated as higher in behavior problems showed deficits in emotional understanding. Intellectual functioning was negatively associated with behavior problems and attenuated the effects of behavior problems on emotional understanding. Implications of the current findings for prevention and treatment programs for children with behavior problems are discussed.
A combination of saturation and site-directed mutagenesis was utilized to disrupt the alpha 2 domain disulfide bridge of HLA-A*0201. Mutation of cysteine 101 to a serine (C101S) or of cysteine 164 to alanine (C164A) decreased the rate of maturation of the heavy chain, the total amount of mature heavy chain within the cell, and the level of surface expression. Cells expressing these genes and loaded with a synthetic peptide derived from the influenza A matrix protein (58-66) were recognized poorly by HLA-A*0201-restricted, peptide-specific CTLs. Cells expressing mutant HLA-A*0201 loaded with a synthetic peptide derived from the HIV-1 pol protein (476-484) were not recognized by pol IV-9-specific CTLs. Mutant C164A cells infected with influenza virus were partially recognized by influenza matrix peptide-specific CTLs, while C101S cells were not lysed. Surprisingly, endogenous peptide loading of cells expressing mutant HLA-A*0201 using a minigene coding for either the influenza A matrix peptide 58-66, or HIV-1 pol peptide 476-484, resulted in efficient CTL recognition. This suggests different structural constraints for peptide binding in the endoplasmic reticulum during biosynthesis and for binding to exported molecules on the cells surface.