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Inhibitors of fibril formation and cytotoxicity of beta-amyloid peptide composed of KLVFF recognition element and flexible hydrophilic disrupting element.

Beta-Amyloid peptide (Abeta) is the main protein components of neuritic plaques and its neurotoxicity would be exposed by formation of aggregate. The aggregation inhibitors composed of an Abeta recognition element (KLVFF) and a flexible hydrophilic disrupting element (aminoethoxy ethoxy acetate and aspartate) are designed and chemically synthesized. The inhibitory effects are examined by a pigment binding assay using Congo red or thioflavin T. The present compounds suppress the formation of aggregate, and the compound DDX3 is an especially effective inhibitor. In addition, the synthesized compounds efficiently suppress the cytotoxicity of Abeta against IMR-32 neuroblastoma cells in vitro.

Amyloid beta-Peptides↗

Attention effects of abrupt-onset precues with central, single-element, and multiple-element precues.

Endogenous and exogenous processes of attention have been inferred with different types of precues used in allocation of attention to a target location. In the present research, a comparison was made between the typical peripheral single-element precue (SEP), a central precue, and a multiple-element precue (MEP) in order to further understanding of the processes involved in allocation of attention. Two precues were used on each trial in these experiments. An abrupt-onset precue appeared with an SEP, an MEP, or a central precue and was followed 50 or 300 ms later by a screen containing a target and two distractor characters. The abrupt-onset precue and the other precue each could be valid or invalid in indicating the location of the target, as in the study by Juola, Koshino, and Warner (1995). Response times to the targets showed that validity effects of the abrupt-onset precue and the MEP or central precue were additive, whereas those of the abrupt-onset precue and the SEP were interactive. These data suggest that, like a central precue, an MEP is an endogenous precue that guides conscious control of attention and has its attentional effects at a different processing level from an SEP, which is an exogenous precue and may compete for attentional resources with an abrupt-onset precue.

Adolescent↗

A new family of retroviral long terminal repeat elements in the human genome identified by their homologies to an element 5' to the spider monkey haptoglobin gene.

A new family of retroviral long terminal repeats that we name Spm-LTR has been identified as a result of DNA sequence comparisons between the entire GenBank databank and an element, SPHP, located 5' to the haptoglobin gene of spider monkeys. The 18 human Spm-LTR sequences so identified fall into three subtypes. There is no sequence similarity between Spm-LTR elements and any endogenous retroviral LTR sequences previously reported except for general features that define LTRs. However, a previously described repeated sequence (MER-4) forms a portion of the Spm-LTR sequence.

Animals↗

Thermodynamic prediction of conserved secondary structure: application to the RRE element of HIV, the tRNA-like element of CMV and the mRNA of prion protein.

An algorithm for prediction of conserved secondary structure of single-stranded RNA is presented. For each RNA of a set of homologous RNAs optimal and suboptimal secondary structures are calculated and stored in a base-pair probability matrix. A multiple sequence alignment is performed for the set of RNAs. The resulting gaps are introduced into the individual probability matrices. These homologous probability matrices are summed to give a consensus probability matrix emphasizing the conserved secondary structure elements of the RNA set. Thus the algorithm combines the advantages of thermodynamic structure prediction by energy minimization with the information obtained from phylogenetic alignment of sequences. The algorithm is applied to three examples. The REV-responsive element of HIV, the structure of which is well known from the literature, was chosen to test the algorithm. The second example is the 3' terminal segment of genomic single-stranded RNAs of cucumber mosaic viruses; a structure similar to that of the related brome mosaic virus was expected and was confirmed. The third example is the prion-protein mRNA from different organisms; the structure of this mRNA is not known. By application of the algorithm highly conserved hairpins were found in the prion-protein mRNA.

Algorithms↗

Human DNA Polymerase-beta Promoter: Phorbol Ester Activation Is Mediated through the cAMP Response Element and cAMP-Response-Element-Binding Protein.

That mammalian DNA polymerase-beta (beta-pol) gene transcription is upregulated by activated ras and also by phorbol ester (TPA) treatment suggests the involvement of protein kinase C in the gene expression control for this DNA repair enzyme. Yet, the core promoters of the human, bovine and rodent beta-pol genes do not have a TPA response element or other binding site for the transcriptional activator AP-1. Instead, these beta-pol promoters appear to be regulated mainly by proteins binding to the cAMP response element (CRE) centered within 50 bp 5' of the transcriptional start site. In this study, the CRE in the human beta-pol promoter was found to mediate TPA upregulation of the cloned promoter in HeLa cell transient expression experiments. To further examine the role of this CRE in TPA stimulation, we used several mutated promoters that were either deficient in protein binding to the CRE or contained extra CRE sites arranged as tandem repeats. All constructs with at least one functional CRE were upregulated by TPA, whereas mutants lacking CRE protein-binding function were not TPA upregulated. Analyses of HeLa nuclear extract DNA-binding proteins indicated that the beta-pol CRE was bound by CRE-binding protein (CREB) family members CREB-1 and activating transcription factor-1, but not by AP-1 or complexes containg AP-1 subunits. These results suggest that CREB, rather than AP-1 proteins, are required for the CRE-mediated TPA activation of the beta-pol promoter.

Journal Article↗

Distribution of 23 elements in the kidney, liver and lungs of workers from a smeltery and refinery in North Sweden exposed to a number of elements and of a control group.

The levels of antimony, arsenic, cadmium, caesium, chromium, cobalt, copper, gold, iron, lanthanum, lead, manganese, mercury, molybdenum, phosphorus, rubidium, scandium, selenium, silver, tellurium, tin, tungsten and zinc in the kidney, liver and lungs of autopsy specimens from exposed workers in North Sweden, as well as from a control group, have been assayed quantitatively. The workers had been exposed to several elements and their compounds, e.g. lead, mercury, arsenic and cadmium, for long periods in arsenic, lead or selenium plants and in a lead or copper smelter. The chemical analysis was by neutron activation analysis and atomic absorption spectrophotometry. Median levels of antimony, arsenic, cadmium, chromium cobalt, lanthanum, lead or selenium in kidney, liver or lungs in the exposed worker group were found to be about 2 to 16 times as great as the corresponding levels for the control group. Long biological half-life values were observed for these elements, especially in lung tissue.

Aged↗

Lead field computation for the electrocardiographic inverse problem--finite elements versus boundary elements.

In order to be able to solve the inverse problem of electrocardiography, the lead field matrix (transfer matrix) has to be calculated. The two methods applied for computing this matrix, which are compared in this study, are the boundary element method (BEM) and the finite element method (FEM). The performance of both methods using a spherical model was investigated. For a comparable discretization level, the BEM yields smaller relative errors compared to analytical solutions. The BEM needs less computation time, but a larger amount of memory. Inversely calculated myocardial activation times using either the FEM or BEM computed lead field matrices give similar activation time patterns. The FEM, however, is also capable of considering anisotropic conductivities. This property might have an impact for future development, when also individual myocardial fiber architecture can be considered in the inverse formulation.

Anisotropy↗

Characterization of the genetic elements controlling lipoprotein(a) concentrations in Mexican Americans. Evidence for at least three controlling elements linked to LPA, the locus encoding apolipoprotein(a).

Analyses of 1163 samples from the San Antonio Family Heart Study revealed several elements of genetic control of lipoprotein(a) (Lp(a)) concentrations in Mexican Americans. Apolipoprotein(a) (apo(a)) isoform size variation was inversely related to Lp(a) concentrations and explained about 22% of total phenotypic variation. Segregation analyses suggested the existence of a major gene that influenced an additional 41% of total Lp(a) variation. A G-->A polymorphism in the LPA promoter was in strong disequilibrium with apo(a) isoform size, but did not contribute a significant amount of additional information about Lp(a) variation. However, about 25% of variation in Lp(a) concentrations was influenced by additive polygenic effects, which include the effects of null phenotype alleles. Altogether, these genetic components explained 89% of Lp(a) variation, similar to heritability estimates made in several other studies. Apo(a) size variation and the major gene (explaining a total of about 62% of Lp(a) variation) were linked to each other and, as expected, to the plasminogen locus. Thus, together with the well-established null phenotype allele, these different genetic factors represent at least three distinct elements of control exerted at the LPA locus, which encodes the apo(a) protein.

Adult↗

Effects of the length ratio between the contractile element and the series elastic element on an explosive muscular performance.

Effects of the length ratio between the contractile element (CE) and the series elastic element (SEE) on the behavior of the muscle tendon complex were investigated during stretch-shortening cycles. A computer simulation model of the Hill-type muscle tendon complex was constructed. The proximal end of the CE was affixed to a point in the gravitational field, and a massless supporting object was affixed to the distal end of the SEE. A mass was held on the supporting object. Initially, the muscle tendon complex was fixed at a certain length, and the CE was activated at 100%. Through this process, the CE contracted as much as the SEE was stretched. Thereafter, the supporting object was released, which caused the muscle tendon complex to propel the mass upward, simulating a stretch-shortening cycle. The length ratio between the CE and the SEE, the size of the mass and the initial length of the CE were sequentially changed. As a result, it was found that a higher performance is obtained with a longer SEE when the mass is small, while with a shorter SEE when the mass is large.

Computer Simulation↗

Periodic systems of molecules as elements of Shchukarev's "supermatrix", i.e. the chemical element periodic system.

Generations of Soviet scientists contributed invaluable insights into molecular classification. Unfortunately, this research is little appreciated in much of the world. Among these workers S. A. Shchukarev was of great importance. His and his followers' legacy includes a host of graphical displays showing enthalpies of formation of gaseous molecules from free atoms DeltaH(a) and standard enthalpies of formation of substances plotted on the atomic number of the central elements, on their oxidation states, their internuclear separations, and other variables for a wide range of molecules. These graphs serve as databases, from which data can be extracted, to moderate precision, visually. We discuss graphs for one very limited set, or "pleiade" (gas-phase oxides of nitrogen), and for three much broader sets, or subsystems (gas-phase fluorides of all main subgroup atoms and oxides of transition-metal atoms in gas-phase and in STP conditions). When dissolved in water, molecules lose their identities but periodicity is echoed in the acids and aquocations that are formed. We show, as an example in tabular form, that redox potentials of high-oxygen acids containing S, Se, and Te change concomitantly with DeltaH(a ) and DeltaH(f) of their hexafluorides. We present graphical evidence that three properties for cations of groups 1-3 (in the short version of the periodic chart) behave similarly and share the periodicity of the elements. One of the properties is related to the ionization potential, which is shown in a tabular example to vary concomitantly with energy of hydration. It was the ultimate goal of S. A. Shchukarev that the transformation of any one graphical database into any other, having different molecules under different conditions, would be made mathematically.

Journal Article↗

DNase I hypersensitivity sites and nuclear protein binding on the fatty acid synthase gene: identification of an element with properties similar to known glucose-responsive elements.

We have shown previously that fatty acid synthase (FAS) gene expression is positively regulated by glucose in rat adipose tissue and liver. In the present study, we have identified in the first intron of the gene a sequence closely related to known glucose-responsive elements such as in the L-pyruvate kinase and S14 genes, including a putative upstream stimulatory factor/major late transcription factor (USF/MLTF) binding site (E-box) (+ 292 nt to + 297 nt). Location of this sequence corresponds to a site of hypersensitivity to DNase I which is present in the liver but not in the spleen. Moreover, using this information from a preliminary report of the present work, others have shown that a + 283 nt to + 303 nt sequence of the FAS gene can confer glucose responsiveness to a heterologous promoter. The protein binding to this region has been investigated in vitro by a combination of DNase I footprinting and gel-retardation experiments with synthetic oligonucleotides and known nuclear proteins. DNase I footprinting experiments using a + 161 nt to + 405 nt fragment of the FAS gene demonstrate that a region from + 290 nt to + 316 nt is protected by nuclear extracts from liver and spleen. This region binds two ubiquitous nuclear factors, USF/MLTF and the CAAT-binding transcription factor/nuclear factor 1 (CTF/NF1). Binding of these factors is similar in nuclear extracts from liver which does or does not express the FAS gene as observed for glucose-responsive elements in the L-pyruvate kinase and S14 genes. This suggests a posttranslational modification of a factor of the complex after glucose stimulation.

Animals↗

Identification of an essential core element and stimulatory sequences in a Kluyveromyces lactis ARS element, KARS101.

A Kluyveromyces lactis chromosomal sequence of 913 bp is sufficient for replication in Saccharomyces cerevisiae and K. lactis. This fragment contains a 12 bp sequence 5'-ATTTATTGTTTT-3' that is related to the S. cerevisiae ACS (ARS consensus sequence). This dodecamer was removed by site-directed mutagenesis and the effect on K. lactis and S. cerevisiae ARS (autonomous replicating sequence) activity was determined. The dodecamer is essential for S. cerevisiae ARS function but only contributes to K. lactis ARS activity; therefore, its role in K. lactis is unlikely to be the same as that of the essential S. cerevisiae ACS. A 103 bp subclone was found to retain ARS activity in both yeasts, but the plasmid was very unstable in S. cerevisiae. Deletion and linker substitution mutagenesis of this fragment was undertaken to define the DNA sequence required for K. lactis ARS function and to test whether the sequence required for ARS activity in K. lactis and S. cerevisiae coincide. We found a 39 bp core region essential for K. lactis ARS function flanked by sequences that contribute to ARS efficiency. The instability of the plasmid in S. cerevisiae made a fine-structure analysis of the S. cerevisiae ARS element impossible. However, the sequences that promote high-frequency transformation in S. cerevisiae overlap the essential core of the K. lactis ARS element but have different end-points.

Base Sequence↗

All-electron and relativistic pseudopotential studies for the group 1 element polarizabilities from K to element 119.

Two-component and scalar relativistic energy-consistent pseudopotentials for the group 1 elements from K to element 119 are presented using nine electrons for the valence space definition. The accuracy of such an approximation is discussed for dipole polarizabilities and ionization potentials obtained at the coupled-cluster level as compared to experimental and all-electron Douglas-Kroll results.

Journal Article↗

Outlined elements, regular elements and coincidences in illusory-figure patterns.

When elements in a pattern which would otherwise produce an illusory figure are modified by outlining or by increasing their regularity (in accordance with a proposed measure of the latter quality), the illusory effect is much reduced. Both results reflect the principle that 'coincidences' in a display play little or no role in the process of segmentation when other circumstances tend to force critical edges to 'belong' to individual elements of the display.

Attention↗

Pineal expression-promoting element (PIPE), a cis-acting element, directs pineal-specific gene expression in zebrafish.

The pineal gland, sharing morphological and biochemical similarities with the retina, plays a unique and central role in the photoneuroendocrine system. The unique development of the pineal gland is directed by a specific combination of the expressed genes, but little is known about the regulatory mechanism underlying the pineal-specific gene expression. We isolated a 1.1-kbp fragment upstream of the zebrafish exo-rhodopsin (exorh) gene, which is expressed specifically in the pineal gland. Transgenic analysis using an enhanced green fluorescent protein reporter gene demonstrated that the proximal 147-bp region of the exorh promoter is sufficient to direct pineal-specific expression. This region contains three copies of a putative cone rod homeobox (Crx)Otx-binding site, which is known to be required for expression of both retina- and pineal-specific genes. Deletion and mutational analyses of the exorh promoter revealed that a previously uncharacterized sequence TGACCCCAATCT termed pineal expression-promoting element (PIPE) is required for pineal-specific promoter activity in addition to the CrxOtx-binding sites. By using the zebrafish rhodopsin (rh) promoter that drives retina-specific expression, we created a reporter construct having ectopic PIPE in the rh promoter at a position equivalent to that in the exorh promoter by introducing five nucleotide changes. Such a slight modification in the rh promoter induced ectopic enhanced green fluorescent protein expression in the pineal gland without affecting its retinal expression. These results identify PIPE as a critical cis-element contributing to the pineal-specific gene expression, in combination with the CrxOtx-binding site(s).

Amino Acid Sequence↗

H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element.

Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, but not to other MHC cis-acting sequences or to mutant region II sequences, similar to the naturally occurring region II factor in mouse cells. The deduced amino acid sequence of H-2RIIBP revealed two putative zinc fingers homologous to the DNA-binding domain of steroid/thyroid hormone receptors. Although sequence similarity in other regions was minimal, H-2RIIBP has apparent modular domains characteristic of the nuclear hormone receptors. Further analyses showed that both H-2RIIBP and the natural region II factor bind to the estrogen response element (ERE) of the vitellogenin A2 gene. The ERE is composed of a palindrome, and half of this palindrome resembles the region II binding site of the MHC CRE. These results indicate that H-2RIIBP (i) is a member of the superfamily of nuclear hormone receptors and (ii) may regulate not only MHC class I genes but also genes containing the ERE and related sequences. Sequences homologous to the H-2RIIBP gene are widely conserved in the animal kingdom. H-2RIIBP mRNA is expressed in many mouse tissues, in agreement with the distribution of the natural region II factor.

Amino Acid Sequence↗

Mouse cytoplasmic polyadenylylation element binding protein: an evolutionarily conserved protein that interacts with the cytoplasmic polyadenylylation elements of c-mos mRNA.

Cytoplasmic polyadenylylation is an essential process that controls the translation of maternal mRNAs during early development and depends on two cis elements in the 3' untranslated region: the polyadenylylation hexanucleotide AAUAAA and a U-rich cytoplasmic polyadenylylation element (CPE). In searching for factors that could mediate cytoplasmic polyadenylylation of mouse c-mos mRNA, which encodes a serine/threonine kinase necessary for oocyte maturation, we have isolated the mouse homolog of CPEB, a protein that binds to the CPEs of a number of mRNAs in Xenopus oocytes and is required for their polyadenylylation. Mouse CPEB (mCPEB) is a 62-kDa protein that binds to the CPEs of c-mos mRNA. mCPEB mRNA is present in the ovary, testis, and kidney; within the ovary, this RNA is restricted to oocytes. mCPEB shows 80% overall identity with its Xenopus counterpart, with a higher homology in the carboxyl-terminal portion, which contains two RNA recognition motifs and a cysteine/histidine repeat. Proteins from arthropods and nematodes are also similar to this region, suggesting an ancient and widely used mechanism to control polyadenylylation and translation.

Amino Acid Sequence↗

Epidermal growth factor induces H+,K+-ATPase alpha-subunit gene expression through an element homologous to the 3' half-site of the c-fos serum response element.

Epidermal growth factor (EGF) acutely inhibits acid secretion; however, prolonged administration of EGF has been reported to increase acid production. We undertook these studies to examine whether the physiological effects of EGF on acid secretion are mediated by regulation of gastric H+,K+-ATPase, the principle enzyme responsible for acid secretion. EGF in concentrations equivalent to those in plasma increased H+,K(+)-ATPase alpha-subunit mRNA levels. Using H+,K(+)-ATPase-luciferase constructs transfected into primary cultured parietal cells, a significant step up in EGF inducibility was observed between bases -162 and -156 (5'-GACATGG-3') relative to the cap site. This EGF response element (ERE) conferred EGF inducibility when linked to homologous and heterologous promoters. The ERE is homologous to the 3' half-site of the c-fos serum response element to which rNFIL-6, rE12, and SRE-ZBP bind. Electrophoretic mobility shift assays using an ERE probe and parietal cell nuclear extracts revealed a specific DNA-protein complex, the formation of which was changed by neither E12 and NFIL-6 consensus oligonucleotides nor antibodies for NFIL-6, SRE-ZBP, and E12. Our studies indicate that EGF induces gastric H+,K(+)-ATPase alpha-subunit gene expression via an interaction between a specific ERE and a novel transcriptional factor and that this may be a physiologic mechanism by which EGF regulates acid secretion.

Aminopyrine↗