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PubMed2024

Multiple Forms and Functions of Premature Termination by RNA Polymerase II.

Eukaryotic genomes are widely transcribed by RNA polymerase II (pol II) both within genes and in intergenic regions. POL II elongation complexes comprising the polymerase, the DNA template and nascent RNA transcript must be extremely processive in order to transcribe the longest genes which are over 1 megabase long and take many hours to traverse. Dedicated termination mechanisms are required to disrupt these highly stable complexes. Transcription termination occurs not only at the 3' ends of genes once a full length transcript has been made, but also within genes and in promiscuously transcribed intergenic regions. Termination at these latter positions is termed "premature" because it is not triggered in response to a specific signal that marks the 3' end of a gene, like a polyA site. One purpose of premature termination is to remove polymerases from intergenic regions where they are "not wanted" because they may interfere with transcription of overlapping genes or the progress of replication forks. Premature termination has recently been appreciated to occur at surprisingly high rates within genes where it is speculated to serve regulatory or quality control functions. In this review I summarize current understanding of the different mechanisms of premature termination and its potential functions.

RNA Polymerase II↗

PubMed2005

Methylphenidate (Ritalin) induces Homer 1a and zif 268 expression in specific corticostriatal circuits.

Corticostriatal circuits participate in limbic, attentional, motor and other networks, and are implicated in psychostimulant addiction. The psychostimulant methylphenidate is used in the treatment of attention-deficit hyperactivity disorder and for recreational purposes. Recent studies indicate that methylphenidate alters gene expression in striatal neurons. We investigated whether methylphenidate affects gene regulation in specific corticostriatal circuits, by comparing drug-induced molecular changes in different functional domains of the striatum with changes in their cortical input regions. In order to assess the potential functional significance of methylphenidate-induced molecular changes, we examined members of two different classes of plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a. Acute methylphenidate administration in adult rats increased the expression of Homer 1a and zif 268 in both cortex and striatum in a dose-dependent and regionally selective manner. These changes in gene expression occurred after doses of 2 mg/kg (i.p.) and higher, and were highly correlated between cortical regions and their striatal targets. In the cortex, increases were maximal in the medial agranular (premotor) and cingulate cortex, followed by motor and somatosensory cortex, and were minimal in the insular cortex. Correspondingly, in the striatum, increases were most robust in sensorimotor sectors that receive medial agranular input, and were weaker or absent in ventral sectors. The methylphenidate-induced increases in cortical Homer 1a and zif 268 expression were also correlated with increases in striatal substance P and dynorphin expression (direct pathway). Overall, the regional distribution of methylphenidate-induced molecular changes in the striatum was similar to that of changes induced by psychostimulants such as cocaine. These findings demonstrate that methylphenidate affects transcription and synaptic plasticity regulatory proteins in specific corticostriatal circuits, including those implicated in attentional functions and psychostimulant addiction. Such methylphenidate-induced gene regulation may contribute to the therapeutic effects and/or abuse liability of this psychostimulant.

Animals↗

PubMed2003

Cryptic organelles in parasitic protists and fungi.

A number of parasitic protists and fungi have adopted extremely specialised characteristics of morphology, biochemistry, and molecular biology, sometimes making it difficult to discern their evolutionary origins. One aspect of several parasitic groups that reflects this is their metabolic organelles, mitochondria and plastids. These organelles are derived from endosymbiosis with an alpha-proteobacterium and a cyanobacterium respectively, and are home to a variety of core metabolic processes. As parasites adapted, new demands, or perhaps a relaxation of demands, frequently led to significant changes in these organelles. At the extreme, the organelles are degenerated and transformed beyond recognition, and are referred to as "cryptic". Generally, there is no prior cytological evidence for a cryptic organelle, and its presence is only discovered through phylogenetic analysis of molecular relicts followed by their localisation to organelle-like structures. Since the organelles are derived from eubacteria, the genes for proteins and RNAs associated with them are generally easily recognisable, and since the metabolic activities retained in these organelles are prokaryotic, or at least very unusual, they often serve as an important target for therapeutics. Cryptic mitochondria are now known in several protist and fungal parasites. In some cases (e.g., Trichomonas), well characterised but evolutionarily enigmatic organelles called hydrogenosomes were shown to be derived from mitochondria. In other cases (e.g., Entamoeba and microsporidia), "amitochondriate" parasites have been shown to harbour a previously undetected mitochondrial organelle. Typically, little is known about the functions of these newly discovered organelles, but recent progress in several groups has revealed a number of potential functions. Cryptic plastids have now been found in a small number of parasites that were not previously suspected to have algal ancestors. One recent case is the discovery that helicosporidian parasites are really highly adapted green alga, but the most spectacular case is the discovery of a plastid in the Apicomplexa. Apicomplexa are very well-studied parasites that include the malaria parasite, Plasmodium, so the discovery of a cryptic plastid in Apicomplexa came as quite a surprise. The apicomplexan plastid is now very well characterised and has been shown to function in the biosynthesis of fatty acids, isopentenyl diphosphate and heme, activities also found in photosynthetic plastids.

Animals↗

PubMed2003

Synthesis of functional olefin copolymers with controllable topologies using a chain-walking catalyst.

The branching topology of ethylene polar copolymers was for the first time successfully controlled by copolymerization of ethylene with polar olefins using a palladium-bisimine chain-walking catalyst, in which ethylene pressure and comonomer concentration were used to control the competition between isomerization (chain-walking) and monomer insertion processes. Although the overall branching density changes very slightly, the topology of the copolymers becomes more dendritic as the ethylene pressure and comonomer feed concentration are decreasing. This provides a straightforward one-pot synthesis to access a full range of functional copolymers having controllable branching topologies. To demonstrate the utility of this methodology, dendritic functional copolymers having hydroxyl, epoxide, and carbohydrate groups were prepared in a one-pot polymerization as potential functional materials.

Journal Article↗

PubMed2026

PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.

Alzheimer Disease↗

PubMed2004

Evaluation of multicenter one-electron integrals of noninteger u screened Coulomb type potentials and their derivatives over noninteger n Slater orbitals.

Multicenter integrals over noninteger n Slater type orbitals with integer and noninteger values of indices u of screened Coulomb type potentials, f(u)(eta,r)=r(u-1)e(-etar), and their first and second derivatives with respect to Cartesian coordinates of the nuclei of a molecule are described. Using complete orthonormal sets of Psi(alpha) exponential type orbitals and rotation transformation of two-center overlap integrals, these integrals are expressed through the noncentral potential functions depending on the molecular auxiliary functions A(k) and B(k). The series expansion formulas derived for molecular integrals of screened Coulomb potentials and their derivatives are especially useful for the computation of multicenter electronic attraction, electric field, and electric field gradient integrals. The convergence of series is tested for arbitrary values of parameters of potentials and orbitals.

Journal Article↗

PubMed1999

Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID.

Coactivators previously implicated in ligand-dependent activation functions by thyroid hormone receptor (TR) include p300 and CREB-binding protein (CBP), the steroid receptor coactivator-1 (SRC-1)-related family of proteins, and the multicomponent TR-associated protein (TRAP) complex. Here we show that two positive cofactors (PC2 and PC4) derived from the upstream stimulatory activity (USA) cofactor fraction act synergistically to mediate thyroid hormone (T3)-dependent activation either by TR or by a TR-TRAP complex in an in vitro system reconstituted with purified factors and DNA templates. Significantly, the TRAP-mediated enhancement of activation by TR does not require the TATA box-binding protein-associated factors of TFIID. Furthermore, neither the pleiotropic coactivators CBP and p300 nor members of the SRC-1 family were detected in either the TR-TRAP complex or the other components of the in vitro assay system. These results show that activation by TR at the level of naked DNA templates is enhanced by cooperative functions of the TRAP coactivators and the general coactivators PC2 and PC4, and they further indicate a potential functional redundancy between TRAPs and TATA box-binding protein-associated factors in TFIID. In conjunction with earlier studies on other nuclear receptor-interacting cofactors, the present study also suggests a multistep pathway, involving distinct sets of cofactors, for activation of hormone responsive genes.

Animals↗

PubMed1998

Evolution of olfactomedin. Structural constraints and conservation of primary sequence motifs.

Olfactomedin is a glycosylated extracellular matrix protein originally identified at the mucociliary surface of the amphibian olfactory neuroepithelium and subsequently localized throughout the mammalian central nervous system. Although olfactomedin homologues have been identified in fish, frog, rat, mouse and human, its function is still unknown. As a first step toward elucidating the function of olfactomedin, sequences of teleost, amphibian and human homologues were compared to identify invariant, and hence, potential functionally important motifs. Previous studies revealed 33% amino acid sequence identity between rat and frog olfactomedin in their carboxyl terminal segments. Further analysis, however, reveals more extensive homologies throughout the molecule. Despite significant sequence divergence, cysteines essential for homo-polymer formation, such as the CXC motif near the amino terminus, are conserved as is the characteristic glycosylation pattern, suggesting that these posttranslational modifications are essential for function. Furthermore, alignment of a region of 53 amino acids of fish, frog, rat and human olfactomedin reveals seven invariant residues including a negatively charged cluster of aspartic and glutamic acid residues. Molecular evolutionary genetic analysis reveals an accelerated rate of nucleotide substitutions in the mammalian lineage. The evolutionary rate at the protein level, however, is constant, indicating that evolution of olfactomedin is constrained by structural limitations. Whereas considerable evolutionary divergence is evident between fish, frog and mammalian olfactomedins, olfactomedins of rat and human show 98% amino acid sequence identity. It appears that an ancestral olfactomedin gene arose before the evolution of terrestrial vertebrates and evolved independently in teleost, amphibian and mammalian lineages. The apparent evolutionary pressure toward conservation of primary structure supports the notion that olfactomedin has an important function in the mammalian nervous system.

Amino Acid Sequence↗

PubMed2005

Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.

Multiple myeloma (MM) is a B-lineage malignancy characterized by diverse genetic subtypes and clinical outcomes. The recurrent immunoglobulin heavy chain (IgH) switch translocation, t(4;14)(p16;q32), is associated with poor outcome, though the mechanism is unclear. Quantitative reverse-transcription-polymerase chain reaction (RT-PCR) for proposed target genes on a panel of myeloma cell lines and purified plasma cells showed that only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in all t(4;14)POS patients. The different transcripts detected, multiple myeloma SET domain containing protein (MMSET I), MMSET II, Exon 4a/MMSET III, and response element II binding protein (RE-IIBP), are produced by alternative splicing and alternative transcription initiation events. Translation of the various transcripts, including those from major breakpoint region 4-2 (MB4-2) and MB4-3 breakpoint variants, was confirmed by transient transfection and immunoblotting. Green fluorescent protein (GFP)-tagged MMSET I and II, corresponding to proteins expressed in MB4-1 patients, localized to the nucleus but not nucleoli, whereas the MB4-2 and MB4-3 proteins concentrate in nucleoli. Cloning and localization of the Exon 4a/MMSET III splice variant, which contains the protein segment lost in the MB4-2 variant, identified a novel protein domain that prevents nucleolar localization. Kinetic studies using photobleaching suggest that the breakpoint variants are functionally distinct from wild-type proteins. In contrast, RE-IIBP is universally dysregulated and also potentially functional in all t(4;14)POS patients irrespective of fibroblast growth factor receptor 3 (FGFR3) expression or breakpoint type.

Carrier Proteins↗

PubMed2004

The structure of a rigorously conserved RNA element within the SARS virus genome.

We have solved the three-dimensional crystal structure of the stem-loop II motif (s2m) RNA element of the SARS virus genome to 2.7-A resolution. SARS and related coronaviruses and astroviruses all possess a motif at the 3' end of their RNA genomes, called the s2m, whose pathogenic importance is inferred from its rigorous sequence conservation in an otherwise rapidly mutable RNA genome. We find that this extreme conservation is clearly explained by the requirement to form a highly structured RNA whose unique tertiary structure includes a sharp 90 degrees kink of the helix axis and several novel longer-range tertiary interactions. The tertiary base interactions create a tunnel that runs perpendicular to the main helical axis whose interior is negatively charged and binds two magnesium ions. These unusual features likely form interaction surfaces with conserved host cell components or other reactive sites required for virus function. Based on its conservation in viral pathogen genomes and its absence in the human genome, we suggest that these unusual structural features in the s2m RNA element are attractive targets for the design of anti-viral therapeutic agents. Structural genomics has sought to deduce protein function based on three-dimensional homology. Here we have extended this approach to RNA by proposing potential functions for a rigorously conserved set of RNA tertiary structural interactions that occur within the SARS RNA genome itself. Based on tertiary structural comparisons, we propose the s2m RNA binds one or more proteins possessing an oligomer-binding-like fold, and we suggest a possible mechanism for SARS viral RNA hijacking of host protein synthesis, both based upon observed s2m RNA macromolecular mimicry of a relevant ribosomal RNA fold.

Binding Sites↗

PubMed2001

[Pseudocontinent colostomy - a manometric study].

The intraluminal pressure in terminal segment of colon has been studied at 42 patients undergone an exterpation of rectum and taken out pseudocontinent colostomy onto a front part of the abdomen. Schmidt's pattern smooth muscle muff, modified in the Clinic Surgery and Coloproctology at MU--Varna, has been transplanted around the colon, taken out as continent colostomy. The intraluminal pressure in the terminal segment of colon has been identified with an index of resistance on the side the smooth muscle muff against the spontaneous evacuation of the colon content. The pressure has been registrated at rest and after the mechanical dillatation of muscle muff. The pressure at the check group of 20 patients with taken out continent colostomy has been investigated manometrically. The basal intraluminal pressure at the patients with a transplanted smooth muscle muff has been 30 +/- 2.9 mmHg at the end of the first postoperative month, as it has been sustained permanent (29.7 +/- 3.0 mmHg) up to the second postoperative jear (0.001). The pressure has been increased up to the mean value of 42 +/- 2.5 mmHg, as it has been sustained at this level for a period of 120 sec. The basal intraluminal pressure at the patients with transplanted smooth muscle muff has been more then four times higher in comparison with the pressure in c. sigmoideum, which has been a prerequisite for stopping of the spontaneous evacuation. A conclusion has been done that the index of resistance in the terminal segment of colon has been depended on a functional potential of the smooth muscle muff directly. The transplanted muff has been an anatomic structure manifested a functional activity in terms of isolation.

Adult↗

PubMedDate not supplied

[The influence of complementary base pair interactions on secondary structure formation and conformational transitions in polynucleotides].

The calculations have been carried out of interaction energy between complementary base pairs of nucleic acids in the function of conformational parametres of double helix (Arnott's parameters) by the method of atom-atom potential functions. Interaction energy as a function of conformational parametres is valley-like and varies little along the bottom of the valley. The regions of interaction energy minima are compared with experimentally determined conformational parametres of nucleic acid double helices. On the basis of calculation results the pathways of conformational transitions between different forms of double-helical polynucleotides are discussed.

Binding Sites↗

PubMed2005

Evolutionary method for the assembly of rigid protein fragments.

Genetic algorithms constitute a powerful optimization method that has already been used in the study of the protein folding problem. However, they often suffer from a lack of convergence in a reasonably short time for complex fitness functions. Here, we propose an evolutionary strategy that can reproducibly find structures close to the minimum of a potential function for a simplified protein model in an efficient way. The model reduces the number of degrees of freedom of the system by treating the protein structure as composed of rigid fragments. The search incorporates a double encoding procedure and a merging operation from subpopulations that evolve independently of one another, both contributing to the good performance of the full algorithm. We have tested it with protein structures of different degrees of complexity, and present our conclusions related to its possible application as an efficient tool for the analysis of folding potentials.

Algorithms↗

PubMed2005

Whole genome shotgun sequencing of Brassica oleracea and its application to gene discovery and annotation in Arabidopsis.

Through comparative studies of the model organism Arabidopsis thaliana and its close relative Brassica oleracea, we have identified conserved regions that represent potentially functional sequences overlooked by previous Arabidopsis genome annotation methods. A total of 454,274 whole genome shotgun sequences covering 283 Mb (0.44 x) of the estimated 650 Mb Brassica genome were searched against the Arabidopsis genome, and conserved Arabidopsis genome sequences (CAGSs) were identified. Of these 229,735 conserved regions, 167,357 fell within or intersected existing gene models, while 60,378 were located in previously unannotated regions. After removal of sequences matching known proteins, CAGSs that were close to one another were chained together as potentially comprising portions of the same functional unit. This resulted in 27,347 chains of which 15,686 were sufficiently distant from existing gene annotations to be considered a novel conserved unit. Of 192 conserved regions examined, 58 were found to be expressed in our cDNA populations. Rapid amplification of cDNA ends (RACE) was used to obtain potentially full-length transcripts from these 58 regions. The resulting sequences led to the creation of 21 gene models at 17 new Arabidopsis loci and the addition of splice variants or updates to another 19 gene structures. In addition, CAGSs overlapping already annotated genes in Arabidopsis can provide guidance for manual improvement of existing gene models. Published genome-wide expression data based on whole genome tiling arrays and massively parallel signature sequencing were overlaid on the Brassica-Arabidopsis conserved sequences, and 1399 regions of intersection were identified. Collectively our results and these data sets suggest that several thousand new Arabidopsis genes remain to be identified and annotated.

Arabidopsis↗

PubMed2025

TripLexicon: prediction and analysis of gene regulatory RNA-DNA interactions.

MOTIVATION: Non-coding RNA (ncRNA) plays a crucial role in gene regulation, including by forming sequence-specific RNA-DNA interactions at gene regulatory elements. One form of interaction takes place via the formation of RNA:DNA:DNA triple helices (triplexes). Accurate computational prediction of triplex formation from nucleotide sequences is an important tool in ncRNA research but remains somewhat inaccessible and complex. To address this, we created TripLexicon, a web-based interface for accessing and analyzing predicted gene regulatory RNA-DNA interactions in human and mouse. RESULTS: Predicted interactions can be accessed from RNA-, DNA-, and region-centric perspectives. For each RNA transcript, visualizations at genome and nucleotide resolution are available, providing insight into target genes and regions, as well as putative functional domains of the transcript. Predicted target genes can immediately be subjected to ontology and pathway enrichment analysis, providing rapid insight into potential functions mediated by the RNA-DNA interactions of the queried transcript. DNA and region queries are designed to identify potentially important ncRNA interactors at sites of interest. AVAILABILITY AND IMPLEMENTATION: TripLexicon is accessible at https://triplexicon.uni-frankfurt.de. This website is free and open to all users and there is no login requirement. All data and code is uploaded to Zenodo: https://zenodo.org/records/17143608 and the code for the webserver is available on Github: https://github.com/SchulzLab/TripLexicon.

Software↗

PubMed2000

Analysis of prolactin-modulated gene expression profiles during the Nb2 cell cycle using differential screening techniques.

BACKGROUND: Rat Nb2-11C lymphoma cells are dependent on prolactin for proliferation and are widely used to study prolactin signaling pathways. To investigate the role of this hormone in the transcriptional mechanisms that underlie prolactin-stimulated mitogenesis, five different techniques were used to isolate differentially expressed transcripts: mRNA differential display, representational difference analysis (RDA), subtractive suppressive hybridization (SSH), analysis of weakly expressed candidate genes, and differential screening of an organized library. RESULTS: About 70 transcripts were found to be modulated in Nb2 cells following prolactin treatment. Of these, approximately 20 represent unknown genes. All cDNAs were characterized by northern blot analysis and categorized on the basis of their expression profiles and the functions of the known genes. We compared our data with other cell-cycle-regulated transcripts and found several new potential signaling molecules that may be involved in Nb2 cell growth. In addition, abnormalities in the expression patterns of several transcripts were detected in Nb2 cells, including the constitutive expression of the immediate-early gene EGR-1. Finally, we compared the differential screening techniques in terms of sensitivity, efficiency and occurrence of false positives. CONCLUSIONS: Using these techniques to determine which genes are differentially expressed in Nb2 lymphoma cells, we have obtained valuable insight into the potential functions of some of these genes in the cell cycle. Although this information is preliminary, comparison with other eukaryotic models of cell-cycle progression enables identification of expression abnormalities and proteins potentially involved in signal transduction, which could indicate new directions for research.

Animals↗

PubMed2000

LaminOss immediate-load implants: I. Introducing osteocompression in dentistry.

Osteocompression is a physiologic principle that has been clinically practiced in orthopedics since the early 1900s. In dentistry, controlled functional osteocompression is the compaction created by the tapping procedure and bone lamination achieved by a sinusoidal screw implant design providing physiologic stimulation due to streaming potentials. Functionally, there is always an applied force acting on bone modified by an implant design, and there is always a resisting force acting on the implant through the viscoelastic properties of trabecular structure. Through biomechanical events in bone, osseous tissue can be stimulated within physiologic limitations by implant design to develop along the lines of compressive forces dependent on the implant load-bearing area to sustain equilibrium. At the cellular level, these biomechanical events act on the cells through a phenomenon known as streaming potentials. This is an electrochemical potential created by the flow of extracellular fluid past a positively charged cell surface. Streaming potentials have a stimulating effect on osteoblasts and osteocytes. This stimulation under acceptable physiologic limits translates to an ordered deposition of osseous tissue that aids in the support of these compressive forces. As a sinusoidal thread design, the LaminOss osteocompressive immediate-load implant (Impladent Ltd, Holliswood, NY) has shown in animal histologic observation 2.5 times greater bone lamination achieved by the function of osteocompression due to the benefits of streaming potentials created by the LaminOss implant design. No evidence of bone necrosis was observed by any of the eight implants.

Alveolar Process↗

PubMed1983

Effects of propranolol on resting and postextrasystolic potentiated left ventricular function in patients with coronary artery disease.

The effect of propranolol on global and segmental left ventricular function at rest and after postextrasystolic potentiation was studied in 12 patients with chest pain. Heart rate was controlled with atrial pacing, and left ventricular cineangiograms were performed before and after 0.15 mg/kg of propranolol. During each ventriculogram a premature ventricular stimulus was introduced by means of a programmed stimulator. Propranolol decreased global left ventricular ejection fraction from 64 +/- 4.5 to 58 +/- 4.6 (p less than 0.03). Postextrasystolic potentiated global ejection fraction was not affected by propranolol (78 +/- 3.5 vs 73.6 +/- 3.4; p = NS). The area ejection fraction of the anteroapical region was decreased after propranolol (64 +/- 4.8 vs 52 +/- 6.5; p less than 0.01); however, the postextrasystolic potentiated area ejection fraction was not affected by propranolol (78 +/- 2.6 vs 71 +/- 4.6; p = NS). Frame by frame analysis of the ventriculograms demonstrated that propranolol depressed global and segmental left ventricular function by affecting the second one-third ejection fraction without influencing the first or third one-third ejection fraction. Propranolol has a small depressant effect on global and segmental left ventricular function in patients with coronary artery disease. Postextrasystolic potentiated global and segmental left ventricular function and early systolic ejection phase indices are not altered by propranolol and therefore may be useful in assessing left ventricular function in patients with coronary artery disease who are taking propranolol.

Cardiac Catheterization↗