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Ultrahigh frame rate retrospective ultrasound microimaging and blood flow visualization in mice in vivo.

To overcome frame rate limitations in high-frequency ultrasound microimaging, new data acquisition techniques have been implemented for 2-D (B-scan) and color flow visualization. These techniques, referred to as retrospective B-scan imaging (RBI) and retrospective color flow imaging (RCFI) are based on the use of the electrocardiogram (ECG) to trigger signal acquisitions. B-scan and color flow images are reconstructed by retrospectively assembling the processed data on a line-by-line basis. Retrospective techniques are used to produce the first in vivo B-scan and color flow images of mouse carotid arteries at frame rates up to 10,000 fps. Retrospective B-scan images of mouse heart were also produced at frame rates of 1000 fps using a version of RBI implemented on a commercial imaging system (Vevo660, VisualSonics, Toronto, ON, Canada). This technology enables detailed in vivo biomechanical studies of dynamic tissues such as the myocardium of the mouse heart with high temporal resolution.

Animals↗

Replication of Theiler's murine encephalomyelitis virus in Xenopus laevis oocytes.

Xenopus laevis oocytes can be used as an alternative system to study replication of Theiler's murine encephalomyelitis virus (TMEV). We have shown that transcript RNA, containing full-length viral genome, can be directly used to programme the oocytes. In the programmed oocytes, there is correct viral translation, polyprotein processing and assembly of capsid proteins leading to the production of infectious TMEV. The vast majority of de novo synthesised virions were found in the medium in which the programmed oocytes were incubated and not in the oocytes.

Animals↗

Nuclear DNA helicase II (RNA helicase A) binds to an F-actin containing shell that surrounds the nucleolus.

Nuclear DNA helicase II (NDH II), alternatively named RNA helicase A (RHA), is an F-actin binding protein that is particularly enriched in the nucleolus of mouse cells. Here, we show that the nucleolar localization of NDH II of murine 3T3 cells depended on an ongoing rRNA synthesis. NDH II migrated out of the nucleolus after administration of 0.05 microg/ml actinomycin D, while nucleolin and the upstream binding factor (UBF) remained there. In S phase-arrested mouse cells, NDH II was frequently found at the nucleolar periphery, where it was accompanied by newly synthesized nucleolar RNA. Human NDH II was mainly distributed through the whole nucleoplasm and not enriched in the nucleoli. However, in the human breast carcinoma cell line MCF-7, NDH II was also found at the nucleolar periphery, together with the tumor suppressor protein p53. Both NDH II and p53 were apparently attached to the F-actin-based filamentous network that surrounded the nucleoli. Accordingly, this subnuclear structure was sensitive to F-actin depolymerizing agents. Depolymerization with gelsolin led to a striking accumulation of NDH II in the nucleoli of MCF-7 cells. This effect was abolished by RNase, which extensively released nucleolus-bound NDH II when added together with gelsolin. Taken together, these results support the idea that an actin-based filamentous network may anchor NDH II at the nucleolar periphery for pre-ribosomal RNA processing, ribosome assembly, and/or transport.

Actins↗

New cationic lipids form channel-like pores in phospholipid bilayers.

Two representatives of a new class of cationic lipids were found to have high pore-forming activity in planar bilayer membranes. These molecules, called BHHD-TADC and BHTD-TADC, have qualitatively similar effects on phospholipid membranes. Addition of 2.5-5 micro M of either of them to the membrane bathing solutions resulted in formation of long-lived anion-selective pores with conductance in the range 0.1-2 nS in 0.1 M KCl. Pore formation was found to be dependent on the potential applied to the membrane. When negative potential was applied to membrane at the side of addition, the rate of pore formation was much lower compared to when the positive potential was applied. Dependence of pore formation on compound concentration was highly nonlinear, indicating that this process requires assembly of molecules in the membrane. Addition of any of these compounds on both sides of the membrane increased the efficiency of pore formation by one to two orders of magnitude. Pore formation was strongly pH dependent. Although pores were formed with high efficiency at pH 6.5, only occasional fluctuations of membrane conductance were observed at pH 7.5. Possible mechanisms of new compounds biological activity are discussed.

Cations↗

Patterns of dysgraphia and the nonlexical spelling process.

This article evaluates the hypothesis that phoneme-grapheme conversion is accomplished by a passive activation device in which the selection of mapping options in the process of assembling orthography is determined by the frequency of usage of that option in the language. The spelling performance of two brain-damaged, acquired dysgraphic patients is interpreted as support for the stated hypothesis.

Agraphia↗

The Sambucus nigra type-2 ribosome-inactivating protein SNA-I' exhibits in planta antiviral activity in transgenic tobacco.

Transgenic tobacco (Samsun NN) plants transformed with a cDNA clone encoding SNA-I' from Sambucus nigra synthesize, and correctly process and assemble, a fully active type-2 ribosome-inactivating protein. Expression of SNA-I' under the control of the 35S cauliflower mosaic virus promoter enhances the plant's resistance against infection with tobacco mosaic virus. In contrast to type-1 ribosome-inactivating proteins, the expression of SNA-I' does not affect the growth and fertility of the transgenic plants and is not accompanied by an increased expression of pathogenesis-related proteins indicating that its antiviral activity most probably differs from that of pokeweed antiviral protein.

Antiviral Agents↗

Baculovirus expression cassette vectors for rapid production of complete human IgG from phage display selected antibody fragments.

For the expression of human intact IgG antibodies, we have constructed a set of baculovirus expression vectors designed to facilitate rapid insertion of heavy and light chain genes of Fab or scFv antibodies derived from phage display antibody libraries. By linking them to human constant or Fc regions, expression of complete human immunoglobulin molecules was achieved in insect cells by infection with recombinant baculovirus. The IgG expression cassette vectors are based on the backbone vector which contains two back to back polyhedron and p10 promoters. The IgG expression cassette elements, including the authentic IgG lambda or kappa and heavy chain signal sequences, as well as light chain (lambda or kappa) and heavy chain constant region genes are combined in a single vector and are controlled by the p10 and polyhedron promoter respectively. Either of VL or Fab-L and VH or Fab-Fd genes from common phage display systems can be directly inserted into one of the cassette vectors through in-frame cloning sites. This design of a single cassette vector combining heavy and light chain expression elements allowed rapid production and secretion of correctly processed and assembled intact immunoglobulins from recombinant baculovirus infected insect cells. The recombinant antibodies showed the expected molecular size of the H2L2 heterodimer in non reducing SDS-PAGE. No apparent differences were found between the expression level of heavy and light chains, and antigen binding function was preserved. For various antibodies, yields between 6 and 18 mg/l IgG were obtained.

Amino Acid Sequence↗

Enzymes involved in the biogenesis of the nematode cuticle.

Nematodes include species that are significant parasites of man, his domestic animals and crops, and cause chronic debilitating diseases in the developing world; such as lymphatic filariasis and river blindness caused by filarial species. Around one third of the World's population harbour parasitic nematodes; no vaccines exist for prevention of infection, limited effective drugs are available and drug resistance is an ever-increasing problem. A critical structure of the nematode is the protective cuticle, a collagen-rich extracellular matrix (ECM) that forms the exoskeleton, and is critical for viability. This resilient structure is synthesized sequentially five times during nematode development and offers protection from the environment, including the hosts' immune response. The detailed characterization of this complex structure; it's components, and the means by which they are synthesized, modified, processed and assembled will identify targets that may be exploited in the future control of parasitic nematodes. This review will focus on the nematode cuticle. This structure is predominantly composed of collagens, a class of proteins that are modified by a range of co- and post-translational modifications prior to assembly into higher order complexes or ECMs. The collagens and their associated enzymes have been comprehensively characterized in vertebrate systems and some of these studies will be addressed in this review. Conversely, the biosynthesis of this class of essential structural proteins has not been studied in such detail in the nematodes. As with all morphogenetic, functional and developmental studies in the Nematoda phylum, the free-living species Caenorhabditis elegans has proven to be invaluable in the characterization of the cuticle and the cuticle collagen gene family, and is now proving to be an excellent model in the study of cuticle collagen biosynthetic enzymes. This model system will be the main focus of this review.

Animals↗

Western blotting with diaminobenzidine detection for the diagnosis of congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are a growing group of genetic disorders caused by a deficient assembly or processing of glycoproteins. Our aim was to improve a western blotting detection procedure previously described and to assess the efficiency of this procedure for CDG screening, using isoelectric focusing (IEF) as the reference method. We analysed transferrin and haptoglobin in serum from 12 patients with CDG-Ia, 3 patients with CDG-X and 95 healthy paediatric controls. These proteins were also studied in dried blood spot samples. Reference values for our paediatric population were established. No differences (Mann-Whitney test) were observed in the percentage of low molecular weight transferrin and haptoglobin fractions according to sex and age of the controls. Densitometric analysis showed a high percentage of the less sialylated fractions of glycoproteins in all CDG-Ia patients and normal values in the CDG-X patients. In conclusion, western blotting with diaminobenzidine detection is a simple and sensitive procedure to screen for CDG, either in serum or blood spot samples. Densitometric analysis and the establishment of reference values might improve the detection of subtle changes in the glycosylation of proteins.

3,3'-Diaminobenzidine↗

High level expression of the capsid protein of hepatitis E virus in diverse eukaryotic cells using the Semliki Forest virus replicon.

The capsid protein of hepatitis E virus (HEV) is encoded by open reading frame 2 (ORF 2) and exhibits variable processing when expressed in insect and COS cells, but nothing is known of its processing in cells relevant to its replication. The full-length ORF 2 protein was expressed at high levels in mammalian cells by insertion of ORF 2 in the Semliki Forest virus (SFV) replicon to generate rSFV/HEV ORF 2K. Expression of the capsid protein was detected readily by metabolic labelling and indirect immunofluorescence in BHK-21 cells transfected with RNA transcripts derived from rSFV/HEV ORF 2K. ORF 2 protein was also expressed at high levels in cells of diverse origin, including liver-derived cell lines Huh7 and HepG2, following infection with recombinant virus derived from cotransfection of BHK-21 cells with the rSFV/HEV ORF 2K and helper SFV replicon RNAs. The addition of hypertonic KCl during metabolic labelling reduced the level of host cell protein synthesis and enhanced the detection of intermediates in ORF 2 protein processing. The wide host range and high level expression directed by SFV replicon particles has particular utility in the analysis of cell-specific factors in the protein processing and assembly of non-cultivable viruses such as HEV.

Animals↗

Huntington's disease gene product, huntingtin, associates with microtubules in vitro.

The gene responsible for Huntington's disease produces a large protein with a molecular weight of approximately 350 k, designated huntingtin. Here, we report that the protein can associate in vitro with the microtubules. Through the process of assembly and disassembly of microtubules, both wild-type and mutant huntingtin associate with microtubules to almost the same degree. Huntingtin does not bind to the tubulin-affinity column directly. Huntingtin appears to interact with polymerized tubulin. These results suggest that huntingtin may have a role in intracellular organelle transport or axonal transport by its association with microtubules.

Adult↗

Elastography imaging of small animal oncology models: a feasibility study.

To test the feasibility of applying ultrasonic elastography on small animal oncology models, experiments were performed in vitro and in situ on murine mammary lesions induced exogenously by tumor cell line 66.3. In vitro studies involved three 1-week-old excised tumors embedded in a phantom block with ultrasonic properties similar to those of soft biologic tissues. In situ studies involved five mice whose bodies were embedded in pure gelatin blocks. The data were acquired from the blocks with a clinical scanner modified to have an automated compressor assembly and processed to construct the elastograms at various imaging planes within each block. The results were analyzed both qualitatively and quantitatively to assess the merits of the elastographic imaging and its limitations for in vivo serial studies of tumors in small animal oncology models.

Animals↗

Identification of a novel human member of the DEAD box protein family.

The cDNA library of human pancreatic islets was screened with sera from patients with insulin-dependent diabetes mellitus (IDDM). From the library screening, we isolated a novel cDNA, RNA helicase-like protein (RHELP), which exhibited strong sequence homology to p68 RNA helicase, a prototypic member of the DEAD (Asp-Glu-Ala-Asp) box protein family. Sequence analysis of the cDNA revealed that RHELP contained DEAD sequence motif and other conserved motifs of the DEAD box protein family, indicating that RHELP is a new member of this family. DEAD box-containing proteins are involved in the RNA processing, ribosome assembly, spermatogenesis, embryogenesis, and cell growth and division. RHELP showed 42% and 44% amino acid sequence identity to human p68 RNA helicase and yeast DBP2 RNA helicase, respectively, among the DEAD box protein family. Northern blot analysis revealed that RHELP is expressed in most tissues including the liver, lung, tonsil, thymus, and muscle in addition to the pancreatic islets. In vivo or in vitro functions of RHELP as a putative RNA helicase and its potential role as a diabetic autoantigen need to be further investigated.

Amino Acid Sequence↗

Immunoglobulin diversity: rearranging by cutting and repairing.

The recombination process that assembles antigen-receptor genes is now understood in some biochemical detail. The initial steps reflect a common theme seen in retroviral integration and prokaryotic transposition, and the later steps involve the enzymatic machinery for double-strand break DNA repair.

Animals↗

The ultrastructure of yeast: cell wall structure and formation.

Yeasts are unicellular eukaryotes, and are used widely as a model system in basic and applied fields of life science, medicine, and biotechnology. The ultrastructure of yeast cells was first studied in 1957 and the techniques used have advanced greatly in the 40 years since then; an overview of these methods is first presented in this review. The ultrastructure of budding and dimorphic yeast cells observed with a scanning electron microscope (SEM) and a transmission electron microscope (TEM) after thin sectioning and freeze-etching are then described, followed by discussion of the regeneration of the cell wall of Candida albicans protoplasts detected by cryosectioning. C. albicans protoplasts are regenerated to synthesize microfibrils on their surface. They are aggregated into thicker bundles which are intermeshed, forming a wide-meshed network of long fibrils. These microfibrillar structures are chains of beta-1,3-glucan which are broken down after treatment with beta-1,3-glucanase. Morphologically identical microfibrils are synthesized in vitro by a cell-free system in which the active cell membrane fraction as a source of beta-1,3-glucan synthetase and UDP glucose as the sole substrate are used. The diameter of an elemental fibril of beta-glucan is estimated to be 2.8 nm from the pattern of autocorrelation of the image obtained by computer processing. In contrast, in the presence of aculeacin A the formation of normal fibrillar nets or bundles is significantly inhibited, resulting in the occurrence of short fibrils. These electron microscopic data suggest that aculeacin A inhibits not only the synthesis of beta-1,3-glucan but the aggregation of microfibrils of this polysaccharide, allowing formation of the crystalline structure. On the basis of the cumulative data obtained from the electron microscopic studies, we are led to the assumption that de novo synthesized beta-glucan chains might initially form fine particles which are then transformed into thin fibrils with single to multiple strands which appear to be oriented parallel to each other so that they develop into fibrillar structures. This process of assembly of beta-glucan molecules leads to the development of a fibrous network within the regenerating Candida cell wall. Third, the mechanism of cell wall formation is shown by low-voltage (LV) SEM and TEM, using various techniques and computer graphics, of the regeneration system of Schizosaccharomyces pombe protoplasts: after 10 min of regeneration, the protoplasts begin to grow fibrillar substances of a beta-glucan nature, and a fibrillar network covers the surface of all protoplasts. The network is originally formed as fine particles on the protoplast surface and these are subsequently lengthened to microfibrils 2 nm thick. The microfibrils twist around each other and develop into 8 nm thick fibrils forming flat bundles 16 nm thick. Interfibrillar spaces are gradually filled with amorphous particles of an alpha-galactomannan nature and, finally, the complete cell wall is formed after 12 h. Treatment of reverting protoplasts with RuO4 provided clear TEM images of glucan fibrils with high electron density. The relationship between cell wall regeneration and intracellular organelles was examined by using serial thin sections stained with PATAg and computer-aided three-dimensional reconstruction. The secretory vesicles in a protoplast had increased markedly by 1.4, 3.4, and 5.8 times at 1.5, 3.0, and 5 h, respectively. Three-dimensional analysis indicates that Golgi apparatuses are located close together in the nucleus of the protoplast and are dispersed into the cytoplasm during the progress of cell wall formation.

Cell Wall↗

Mutation processes at the protein level: is Lamarck back?

The experimental evidence accumulated for the last half of the century clearly suggests that inherited variation is not restricted to the changes in genomic sequences. The prion model, originally based on unusual transmission of certain neurodegenerative diseases in mammals, provides a molecular mechanism for the template-like reproduction of alternative protein conformations. Recent data extend this model to protein-based genetic elements in yeast and other fungi. Reproduction and transmission of yeast protein-based genetic elements is controlled by the "prion replication" machinery of the cell, composed of the protein helpers responsible for the processes of assembly and disassembly of protein structures and multiprotein complexes. Among these, the stress-related chaperones of Hsp100 and Hsp70 groups play an important role. Alterations of levels or activity of these proteins result in "mutator" or "antimutator" affects in regard to protein-based genetic elements. "Protein mutagens" have also been identified that affect formation and/or propagation of the alternative protein conformations. Prion-forming abilities appear to be conserved in evolution, despite the divergence of the corresponding amino acid sequences. Moreover, a wide variety of proteins of different origins appear to possess the ability to form amyloid-like aggregates, that in certain conditions might potentially result in prion-like switches. This suggests a possible mechanism for the inheritance of acquired traits, postulated in the Lamarckian theory of evolution. The prion model also puts in doubt the notion that cloned animals are genetically identical to their genome donors, and suggests that genome sequence would not provide a complete information about the genetic makeup of an organism.

Animals↗

Stopped-flow, classical, and dynamic light scattering analysis of matrix protein binding to nucleocapsids of vesicular stomatitis virus.

During the process of assembly of enveloped viruses, binding of the nucleoprotein core of the virus (nucleocapsid) to the host membrane is mediated by the viral matrix (M) protein. Light scattering properties of vesicular stomatitis virus (VSV) nucleocapsids and nucleocapsid-M protein (NCM) complexes assembled in vivo were determined following solubilizaton of the virion envelope with detergents at varying ionic strength to vary the extent of M protein binding. Three factors were found to contribute to the light scattering properties of VSV nucleocapsids: their conformation, extent of self-association, and amount of bound M protein. All three were affected by changes in ionic strength but could be distinguished by several parameters. Conformational changes in nucleocapsids and NCM complexes occurred rapidly (millisecond time scale) upon changing salt concentration and were reflected in changes in the angular dependence of light scattering intensity (i.e., changes in radius of gyration, RG). Changes in extent of self-association occurred relatively slowly (seconds to minutes time scale) and could be distinguished by the concentration dependence of the apparent molecular mass and diffusion coefficient of the NCM complex. Changes in M protein binding occurred on an intermediate time scale (t1/2 approximately one s) and reflected changes in both molecular mass and RG. The data presented here provide criteria for assessing binding of M protein to nucleocapsids under conditions of minimal perturbation of the NCM complex assembled in vivo and at low protein concentrations so that self-association of the NCM complex was minimal and reversible.

Animals↗

Total synthesis and structural elucidation of azaspiracid-1. Final assignment and total synthesis of the correct structure of azaspiracid-1.

The molecular structure of azaspiracid-1, a neurotoxin isolated from mussels, has been elucidated by total synthesis which also enriched its supplies. The degradatively derived fragments of this marine biotoxin, compounds 5 (EFGHI), 6 (FGHI), and 40 (ABCD), were matched with synthetic materials, thus confirming their structural identities. Based on this detective work, a new structure of azaspiracid-1 (i.e., 1) was proposed and constructed by total synthesis. The final strategy for the total synthesis of azaspiracid-1 featured a dithiane anion (C(21)-C(27) fragment) reacting with a pentafluorophenol ester (C(1)-C(20) fragment) followed by a Stille-type union of an advanced allylic acetate substrate (C(1)-C(27) fragment) with a vinyl stannane as the main coupling processes to assemble the carbon skeleton of the molecule. In addition to the total synthesis of azaspiracid-1 (1), the syntheses of its C(1)-C(20) epimer (2) and of several truncated analogues for biological investigations are described.

Animals↗