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PubMed1984

Nuclear genes coding for four subunits of the yeast ubiquinol-cytochrome c reductase complex are present in single copies in the haploid genome and at least two of these are located on different chromosomes.

Genes coding for the 40 kilodaltons (kDa), 17-kDa, 14-kDa and 11-kDa subunits of the ubiquinol-cytochrome c reductase in yeast are present in single copies in the haploid genome. We have mapped each gene to a unique genomic environment and demonstrate that integration of cloned segments into nuclear DNA by homologous crossing-over with the endogenous gene results in the replacement of the corresponding chromosomal restriction fragment by fragments of predicted sizes. Chromosomal mapping, carried out by the procedure of Falco and Botstein 1983, indicates that the gene for the 17-kDa subunit lies on chromosome VI and that for the 11-kDa subunit on chromosome XII.

Chromosome Mapping↗

PubMed2005

Traffic of Kv4 K+ channels mediated by KChIP1 is via a novel post-ER vesicular pathway.

The traffic of Kv4 K+ channels is regulated by the potassium channel interacting proteins (KChIPs). Kv4.2 expressed alone was not retained within the ER, but reached the Golgi complex. Coexpression of KChIP1 resulted in traffic of the channel to the plasma membrane, and traffic was abolished when mutations were introduced into the EF-hands with channel captured on vesicular structures that colocalized with KChIP1(2-4)-EYFP. The EF-hand mutant had no effect on general exocytic traffic. Traffic of Kv4.2 was coat protein complex I (COPI)-dependent, but KChIP1-containing vesicles were not COPII-coated, and expression of a GTP-loaded Sar1 mutant to block COPII function more effectively inhibited traffic of vesicular stomatitis virus glycoprotein (VSVG) than did KChIP1/Kv4.2 through the secretory pathway. Therefore, KChIP1seems to be targeted to post-ER transport vesicles, different from COPII-coated vesicles and those involved in traffic of VSVG. When expressed in hippocampal neurons, KChIP1 co-distributed with dendritic Golgi outposts; therefore, the KChIP1 pathway could play an important role in local vesicular traffic in neurons.

Animals↗

PubMed1992

The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains.

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a multifunctional protein containing two enzymes that act sequentially to catalyze the alpha-amidation of neuroendocrine peptides. Peptidylglycine alpha-hydroxylating monooxygenase (PHM) catalyzes the first step of the reaction and is dependent on copper, ascorbate, and molecular oxygen. Peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) catalyzes the second step of the reaction. Previous studies demonstrated that alternative splicing results in the production of bifunctional PAM proteins that are integral membrane or soluble proteins as well as soluble monofunctional PHM proteins. Rat PAM is encoded by a complex single copy gene that consists of 27 exons and encompasses more than 160 kilobases (kb) of genomic DNA. The 12 exons comprising PHM are distributed over at least 76 kb genomic DNA and range in size from 49-185 base pairs; four of the introns within the PHM domain are over 10 kb in length. Alternative splicing in the PHM region can result in a truncated, inactive PHM protein (rPAM-5), or a soluble, monofunctional PHM protein (rPAM-4) instead of a bifunctional protein. The eight exons comprising PAL are distributed over at least 19 kb genomic DNA. The exons encoding PAL range in size from 54-209 base pairs and have not been found to undergo alternative splicing. The PHM and PAL domains are separated by a single alternatively spliced exon surrounded by lengthy introns; inclusion of this exon results in the production of a form of PAM (rPAM-1) in which endoproteolytic cleavage at a paired basic site can separate the two catalytic domains. The exon following the PAL domain encodes the trans-membrane domain of PAM; alternative splicing at this site produces integral membrane or soluble PAM proteins. The COOH-terminal domain of PAM is comprised of a short exon subject to alternative splicing and a long exon encoding the final 68 amino acids present in all bifunctional PAM proteins along with the entire 3'-untranslated region. Analysis of hybrid cell panels indicates that the human PAM gene is situated on the long arm of chromosome 5.

Animals↗

PubMed1984

Detection of displacement ("D") loops with the properties of a replicating intermediate synthesized by a DNA/membrane complex derived from the low-copy-number plasmid RK2.

A significant fraction of the plasmid DNA extracted from an RK2 miniplasmid DNA/membrane complex after incubation in vitro with appropriate substrates and cofactors contains "D" or displacement loops in one of at least three loci in the genome. These include the origin of replication and two transposon regions that code for kanamycin and tetracycline resistance. The relationship of these loops to early replicating intermediates for plasmid and transposon replication is discussed.

DNA Replication↗

PubMed1998

Rotated drawing: the range of performance and anatomical correlates in a series of 16 patients.

Recently there has been interest in an unusual neuropsychological disorder in which the patient copies a complex drawing in a position which is grossly rotated relative to the original. This disorder is of interest partly because of its relationship to current theories of the process of object recognition, but the range of performances typically seen, as well as its anatomical correlates, remain obscure. We report 16 cases who produced grossly rotated drawings of the Rey and Taylor Complex Figures. These patients were drawn from an unselected series of 240 cases, with a wide variety of lesion types and sites. The performances of the 16 patients displayed striking similarities. We describe the formal features of these drawings and plot their anatomical correlates.

Adolescent↗

PubMedDate not supplied

Fine motor retardation and depression.

New computerized techniques allow the precise measurement of psychomotor retardation in patients with a major depressive episode (MDE). One such technique is the analysis of writing and drawing behaviour during figure copying tasks. In the present study, 22 inpatients with an MDE were compared to 22 normal controls. Three tasks were used: the drawing of lines and simple figures, the copying of complex figures and a task in which figures had to be rotated. Objectives were to provide support for earlier findings that the patients were slower than the controls and to explore the cognitive and motor processes involved. Two strategies were applied: analysis of the reaction time and movement time and their different components, and manipulation of the cognitive and motor demands. Patients showed considerable retardation with most of the kinematic variables. Motor deficits and cognitive slowing down contributed to this retardation. Cognitive difficulties increased with increasing complexity of the task.

Adult↗

PubMedDate not supplied

Extrachromosomal circular DNAs and genomic sequence plasticity in eukaryotic cells.

The ability of eukaryotic organisms of the same genotype to vary in developmental pattern or in phenotype according to varying environmental conditions is frequently associated with changes in extrachromosomal circular DNA (eccDNA) sequences. Although variable in size, sequence complexity, and copy number, the best characterized of these eccDNAs contain sequences homologous to chromosomal DNA which indicates that they might arise from genetic rearrangements, such as homologous recombination. The abundance of repetitive sequence families in eccDNAs is consistent with the notion that tandem repeats and dispersed repetitive elements participate in intrachromosomal recombination events. There is also evidence that a fraction of this DNA has characteristics similar to retrotransposons. It has been suggested that eccDNAs could reflect altered patterns of gene expression or an instability of chromosomal sequences during development and aging. This article reviews some of the findings and concepts regarding eccDNAs and sequence plasticity in eukaryotic genomes.

Animals↗

PubMed2004

Speed and accuracy on tests of executive function in obsessive-compulsive disorder.

Slowness in obsessive-compulsive disorder (OCD) has been attributed to intrusive thoughts or meticulousness. Recent research suggests that slowness in OCD may be particularly evident on tests of executive function subserved by frontostriatal circuitry. In the present study, the speed and accuracy of responding on neuropsychological tests of executive functions and psychomotor speed were investigated in 27 non-depressed, unmedicated adults with OCD and 27 healthy controls. The only group difference was that patients took significantly longer to copy a complex geometric design than controls. This finding was unrelated to residual depression or overall OCD symptom severity. Results suggest that slowness in OCD may be most apparent on executive tests requiring self-initiated organizational strategies, consistent with frontostriatal abnormality.

Adult↗

PubMed2005

Cdc42-dependent localization of polarisome component Spa2 to the incipient bud site is independent of the GDP/GTP exchange factor Cdc24.

Cdc42, a member of the Rho subfamily of small GTPases, is highly conserved in both sequence and function across eukaryotic species. In budding yeast, Cdc42 triggers polarized growth necessary for bud emergence via rearrangement of the actin cytoskeleton. It has been shown that the role of Cdc42 in bud emergence requires both Cdc28-Cln (G1) kinase and the passage through START. In this report, we show that Cdc42 also serves an essential function in the establishment of bud site prior to START by catalyzing the translocation of bud-site components such as Spa2 to the cell cortex. Our analysis of various conditional alleles of CDC42 suggests that these two functions (bud site establishment and bud emergence) are genetically separable. Surprisingly, the role of Cdc42 in the cortical localization of Spa2 appears to be independent of its well known GTP/GDP exchange factor Cdc24. We also provide evidence that this role of Cdc42 requires the function of the COPI coatomer complex.

Alleles↗

PubMedDate not supplied

A screening test for subtle cognitive impairment early in the course of HIV infection.

The authors report on the use of the Rey-Osterrieth Complex Figure Copy (ROC) and Memory (ROM) test as a bedside screening measure of cognitive impairment in 67 HIV-seropositive persons (43 men, 24 women). HIV-seropositive individuals scored significantly worse than 49 HIV-seronegative matched individuals (33 men, 16 women) in the control group on the ROC (P = 0.045, effect size = 0.39), but not on the ROM test. The scores did not correlate with stage of HIV infection, CD4a cell counts, cerebrospinal fluid parameters, or measures of affective state. No gender effects on performance were noted. It is concluded that while cognitive deficits may occur early in asymptomatic HIV disease, the ROC/ROM test as the authors used it is not a useful screening tool for clinicians. The study also suggests that the growing number of HIV-positive women should be included in neuropsychological studies of early HIV disease.

Adolescent↗

PubMed2003

De novo formation, fusion and fission of mammalian COPII-coated endoplasmic reticulum exit sites.

Transport between the endoplasmic reticulum (ER) and Golgi is mediated by the sequential action of the COPII and COPI coat complexes. COPII subunits are recruited to the ER membrane where they mediate the selection of cargo for transport to the Golgi, and also membrane deformation and vesicle formation. New ER exit sites can be generated by lateral growth and medial fission (in Pythium sp.) or by de novo formation (in Pichia pastoris) but it is not known how mammalian ER exit sites form. Here, time-lapse imaging of COPII-coated structures in live mammalian cells reveals that the number of ER export sites increases greatly during interphase by de novo formation. These results show the fusion of pre-existing ER export sites and the fission of larger structures. These three mechanisms of de novo formation, fusion and fission probably cooperate to regulate the size of these sites in mammalian cells.

Animals↗

PubMed1998

Coatomer, Arf1p, and nucleotide are required to bud coat protein complex I-coated vesicles from large synthetic liposomes.

Synthetic coat protein complex I (COPI)-coated vesicles form spontaneously from large ( approximately 300 nm in diameter), chemically defined liposomes incubated with coatomer, Arf1p, and guanosine 5'-[gamma-thio]triphosphate. Coated vesicles are 40-70 nm in diameter, approximately the size of COPI vesicles formed from native membranes. The formation of COPI-coated buds and vesicles and the binding of Arf1p to donor liposomes depends on guanosine 5'-[gamma-thio]triphosphate. In contrast to the behavior of the COPII coat, coatomer binds to liposomes containing a variety of charged or neutral phospholipids. However, the formation of COPI buds and vesicles is stimulated by acidic phospholipids. In the absence of Arf1p, coatomer binds to liposomes containing dioleoylphosphatidic acid as a sole acidic phospholipid to form large coated surfaces without forming COPI-coated buds or vesicles. We conclude that Arf1p-GTP and coatomer comprise the minimum apparatus necessary to create a COPI-coated vesicle.

ADP-Ribosylation Factor 1↗

PubMed1994

Effect of attentional bias to right space on wheelchair mobility.

The impact of hemispatial neglect on wheelchair navigation was investigated using a wheelchair obstacle course. The results replicated the findings of Webster et al. (1988): Right-CVA patients with hemispatial neglect (n = 25) struck more objects on their left and ran directly into obstacles placed in their path (p < .0001). Right-CVA patients who did not omit left-space targets on letter cancellation (n = 23) did not run directly into obstacles; however, they did sideswipe more obstacles and struck more left-sided obstacles than did left-CVA (n = 20) and nonpatient controls (n = 19; p < .0001). Both hemi-neglecting patients and right-CVA patients who committed left-space sideswipes (n = 12) evidenced attentional bias to right space, as measured by more rightward starting points on letter cancellation and the Rey-Osterreith Complex Figure copy (p < .0001).

Aged↗

PubMed2005

Circadian preference and cognitive functioning among rehabilitation inpatients.

The influence of circadian preference was examined among 56 morning-oriented rehabilitation inpatients with cognitive (n=28) and noncognitive (n=28) impairments. Each individual was tested twice: morning (preferred time) and evening (nonpreferred time); sessions and test batteries were counterbalanced to control for practice effects. Standard measures assessed attention, language, memory, visuospatial, and executive functions. Persons with cognitive impairment showed disproportionate vulnerability to the effects of circadian preference and time of testing, performing more poorly at nonpreferred than preferred times. Substantial effects (eta2 .12 to .48) were found on tests of executive functioning and tasks incorporating similar higher-order demands (e/g/. complex figure copy). Results are supported by tympanic temperature changes during a vigilance task, and index of cerebral blood flow in response to cognitive challenge. Cognitive reserve theory is suggested as an explanation for the differential effects. These findings may have implications for inpatient therapeutic interventions and discharge planning.

Adult↗

PubMed2000

Mutants affecting the structure of the cortical endoplasmic reticulum in Saccharomyces cerevisiae.

We find that the peripheral ER in Saccharomyces cerevisiae forms a dynamic network of interconnecting membrane tubules throughout the cell cycle, similar to the ER in higher eukaryotes. Maintenance of this network does not require microtubule or actin filaments, but its dynamic behavior is largely dependent on the actin cytoskeleton. We isolated three conditional mutants that disrupt peripheral ER structure. One has a mutation in a component of the COPI coat complex, which is required for vesicle budding. This mutant has a partial defect in ER segregation into daughter cells and disorganized ER in mother cells. A similar phenotype was found in other mutants with defects in vesicular trafficking between ER and Golgi complex, but not in mutants blocked at later steps in the secretory pathway. The other two mutants found in the screen have defects in the signal recognition particle (SRP) receptor. This receptor, along with SRP, targets ribosome-nascent chain complexes to the ER membrane for protein translocation. A conditional mutation in SRP also disrupts ER structure, but other mutants with translocation defects do not. We also demonstrate that, both in wild-type and mutant cells, the ER and mitochondria partially coalign, and that mutations that disrupt ER structure also affect mitochondrial structure. Our data suggest that both trafficking between the ER and Golgi complex and ribosome targeting are important for maintaining ER structure, and that proper ER structure may be required to maintain mitochondrial structure.

Actins↗

PubMed2003

Requirement for neo1p in retrograde transport from the Golgi complex to the endoplasmic reticulum.

Neo1p from Saccharomyces cerevisiae is an essential P-type ATPase and potential aminophospholipid translocase (flippase) in the Drs2p family. We have previously implicated Drs2p in protein transport steps in the late secretory pathway requiring ADP-ribosylation factor (ARF) and clathrin. Here, we present evidence that epitope-tagged Neo1p localizes to the endoplasmic reticulum (ER) and Golgi complex and is required for a retrograde transport pathway between these organelles. Using conditional alleles of NEO1, we find that loss of Neo1p function causes cargo-specific defects in anterograde protein transport early in the secretory pathway and perturbs glycosylation in the Golgi complex. Rer1-GFP, a protein that cycles between the ER and Golgi complex in COPI and COPII vesicles, is mislocalized to the vacuole in neo1-ts at the nonpermissive temperature. These phenotypes suggest that the anterograde protein transport defect is a secondary consequence of a defect in a COPI-dependent retrograde pathway. We propose that loss of lipid asymmetry in the cis Golgi perturbs retrograde protein transport to the ER.

Adenosine Triphosphatases↗

PubMed2003

Genetic analysis of wild-isolated Neurospora crassa strains identified as dominant suppressors of repeat-induced point mutation.

Repeat-induced point mutation (RIP) in Neurospora results in inactivation of duplicated DNA sequences. RIP is thought to provide protection against foreign elements such as retrotransposons, only one of which has been found in N. crassa. To examine the role of RIP in nature, we have examined seven N. crassa strains, identified among 446 wild isolates scored for dominant suppression of RIP. The test system involved a small duplication that targets RIP to the easily scorable gene erg-3. We previously showed that RIP in a small duplication is suppressed if another, larger duplication is present in the cross, as expected if the large duplication competes for the RIP machinery. In two of the strains, RIP suppression was associated with a barren phenotype--a characteristic of Neurospora duplications that is thought to result in part from a gene-silencing process called meiotic silencing by unpaired DNA (MSUD). A suppressor of MSUD (Sad-1) was shown not to prevent known large duplications from impairing RIP. Single-gene duplications also can be barren but are too short to suppress RIP. RIP suppression in strains that were not barren showed inheritance that was either simple Mendelian or complex. Adding copies of the LINE-like retrotransposon Tad did not affect RIP efficiency.

Blotting, Southern↗

PubMed2006

Comparative testing and pharmacovigilance of biosimilars.

Unlike traditional generic pharmaceuticals, biosimilars (also called 'follow-on biopharmaceuticals' in the USA) aim to copy a complex recombinant, three-dimensional protein structure with high molecular weight. Small changes in the manufacturing process can alter the product's effect and safety. According to the guidelines of the European Agency for the Evaluation of Medicinal products (EMEA), extensive comparability testing will be required to demonstrate that the biosimilar has a comparable profile in terms of quality, safety and efficacy as the reference product. Various analytical assays are available to compare physicochemical and biological properties between production batches of a potentially similar biopharmaceutical (comparability) and in comparison with a reference product (similarity). It is important to recognize the limits of existing assays so that the results can be accurately interpreted for market authorization. This article examines the quality and limits of such analytical methods. The analytical tests to demonstrate comparability and similarity of a biosimilar product to a reference drug with respect to protein content, activity, physiochemical integrity, stability, impurities and additives, as well as immunogenicity are discussed. Although several assays are available, reliable tests for safety and efficacy still require development. Furthermore, international standards are missing and materials and methods differ from laboratories making the comparison of results very difficult. Clinical trials and post-authorization pharmacovigilance are essential to guarantee the product's safety and efficacy over time. Pharmacovigilance, as part of a comprehensive risk management programme, will need to include regular testing for consistent manufacturing of the drug.

Drugs, Generic↗