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PubMed2006

DNPTrapper: an assembly editing tool for finishing and analysis of complex repeat regions.

BACKGROUND: Many genome projects are left unfinished due to complex, repeated regions. Finishing is the most time consuming step in sequencing and current finishing tools are not designed with particular attention to the repeat problem. RESULTS: We have developed DNPTrapper, a shotgun sequence finishing tool, specifically designed to address the problems posed by the presence of repeated regions in the target sequence. The program detects and visualizes single base differences between nearly identical repeat copies, and offers the overview and flexibility needed to rapidly resolve complex regions within a working session. The use of a database allows large amounts of data to be stored and handled, and allows viewing of mammalian size genomes. The program is available under an Open Source license. CONCLUSION: With DNPTrapper, it is possible to separate repeated regions that previously were considered impossible to resolve, and finishing tasks that previously took days or weeks can be resolved within hours or even minutes.

Algorithms↗

PubMed1998

The reverse transcriptase component of the Tetrahymena telomerase ribonucleoprotein complex.

Telomerase is a eukaryotic reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. We describe here the identification of a Tetrahymena telomerase protein with reverse transcriptase motifs, p133. This subunit is associated with the previously identified Tetrahymena telomerase RNA and the telomerase proteins p80 and p95 in immunoprecipitation assays. Therefore, all four known Tetrahymena telomerase components are present in a single complex. Expressed in rabbit reticulocyte lysate, recombinant p133 and telomerase RNA alone catalyze a reverse transcriptase activity with some similarities to and some differences from native Tetrahymena telomerase. These experiments suggest a complexity of telomerase structure and function.

Amino Acid Sequence↗

PubMed2005

Structure of the cytochrome b6f complex: new prosthetic groups, Q-space, and the 'hors d'oeuvres hypothesis' for assembly of the complex.

3-A crystal structures of the cytochrome b6f complex have provided a structural framework for the photosynthetic electron transport chain. The structures of the 220,000 molecular weight dimeric cytochrome b6f complex from the thermophilic cyanobacterium, Mastigocladis laminosus (Kurisu et al. 2003, Science 302: 1009-1014), and the green alga, Chlamydomonas reinhardtii (Stroebel et al. 2003, Nature 426: 413-418), are very similar. The latter is the first structure of a integral membrane photosynthetic electron transport complex from a eukaryotic source. The M. laminosus and C. reinhardtii structures have provided structural information and experimental insights to the properties and functions of three native and novel prosthetic groups, a chlorophyll a, a beta-carotene, and a unique heme x, one copy of which is found in each monomer of the cytochrome b6f complex, but not the cytochrome bc1 complex from the mitochondrial respiratory chain of animals and yeast. Several functional insights have emerged from the structures including the function of the dimer; the properties of heme x; the function of the inter-monomer quinone-exchange cavity; a quinone diffusion pathway through relatively narrow crevices or portals; a modified reaction scheme for n-side quinone redox reactions; a necessarily novel mechanism for quenching of the bound chlorophyll triplet state; a possible role for the bound chlorophyll a in activation of the LHC kinase; and a structural and assembly role for the four small PetG, L, M, and N subunits. An 'hors d'oeuvres hypothesis' for assembly of the complex is proposed for the small 'hydrophobic stick' or 'picket fence' polypeptides at the periphery of the complex, based on the cis-positive orientation of the small hydrophobic subunits and the 'toothpick' binding mode of the beta-carotene.

Animals↗

PubMed1999

Reduction of viral load and immune complex load on CD4+ lymphocytes as a consequence of highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patients.

BACKGROUND AND OBJECTIVES: Human immunodeficiency virus (HIV)-induced immune complex load on circulating CD4+ blood lymphocytes is associated with dysfunction and depletion of CD4+ lymphocytes and with increased monocyte/macrophage function. It was investigated whether HAART reduces both the viral load in plasma and the number of immune complex-coated CD4+ lymphocytes in the blood, and whether CD4+ counts are associated with viral load and/or immune complex load. MATERIALS AND METHODS: Twelve HIV+ hemophilia patients before and after conversion to HAART (group 1); eight HIV+ hemophilia patients without antiretroviral therapy (group 2). HIV-1 RNA copies in plasma using NASBA/Nuclisens kits; CD4+ lymphocytes coated in-vivo with immune complexes using flowcytometry on whole blood samples; in-vitro responses of immune complex-coated T lymphocytes in cell culture assays. RESULTS: After conversion to HAART there was a significant reduction of viral load, CD4+ gp120+, CD4+ IgM+, and CD4+ IgG+ circulating blood lymphocytes and plasma neopterin, paralleled by a significant increase of CD4+ and CD8+ counts. The percentage of immune complex-coated CD4+ lymphocytes of converted patients was significantly associated with CD4+ counts, in-vitro responses to concanavalin A (Con A), pokeweed mitogen (PWM), phytohaemagglutinin (PHA), anti-CD3 and pooled allogeneic stimulator cells, and with plasma neopterin levels. CONCLUSION: HAART reduces viral load and HIV-induced immune complex load on circulating CD4+ blood lymphocytes. The results of this study can be interpreted to suggest that HAART increases CD4+ lymphocyte counts in part by counteracting HIV-induced autoimmune phenomena.

Anti-HIV Agents↗

PubMed1996

The product of the Saccharomyces cerevisiae RSS1 gene, identified as a high-copy suppressor of the rat7-1 temperature-sensitive allele of the RAT7/NUP159 nucleoporin, is required for efficient mRNA export.

RAT7/NUP159 was identified previously in a screen for genes whose products are important for nucleocytoplasmic export of poly(A)+ RNA and encodes an essential nucleoporin. We report here the identification of RSS1 (Rat Seven Suppressor) as a high-copy extragenic suppressor of the rat7-1 temperature-sensitive allele. Rss1p encodes a novel essential protein of 538 amino acids, which contains an extended predicted coiled-coil domain and is located both at nuclear pore complexes (NPCs) and in the cytoplasm. RSS1 is the first reported high-copy extragenic suppressor of a mutant nucleoporin. Overexpression of Rss1p partially suppresses the defects in nucleocytoplasmic export of poly(A)+ RNA, rRNA synthesis and processing, and nucleolar morphology seen in rat7-1 cells shifted to the nonpermissive temperature of 37 degrees C and, thus, restores these processes to levels adequate for growth at a rate approximately one-half that of wild-type cells. After a shift to 37 degrees C, the mutant Rat7-1p/Nup159-1p is lost from the nuclear rim of rat7-1 cells and NPCs, which are clustered together in these cells grown under permissive conditions become substantially less clustered. Overexpression of Rss1p did not result in retention of the mutant Rat7-1p/Nup159-1p in NPCs, but it did result in partial maintenance of the NPC-clustering phenotype seen in mutant cells. Depletion of Rss1p by placing the RSS1 open reading frame (ORF) under control of the GAL1 promoter led to cessation of growth and nuclear accumulation of poly(A)+ RNA without affecting nuclear protein import or nuclear pore complex distribution, suggesting that RSS1 is directly involved in mRNA export. Because both rat7-1 cells and cells depleted for Rss1p are defective in mRNA export, our data are consistent with both gene products playing essential roles in the process of mRNA export and suggest that Rss1p overexpression suppresses the growth defect of rat7-1 cells at 37 degrees C by acting to maintain mRNA export.

Alleles↗

PubMed1987

Electron-microscopic studies on location of SH-groups in mitochondrial F1-ATPase using a ferritin label.

A new approach has been suggested for electron-microscopic study of the structure of mitochondrial F1-ATPase based on ferritin labeling. By means of sequential treatment with 2-iminothiolane and Nbs2 we obtained a modified ferritin (NbsSPrCNH-Ft) able to react with SH-groups of proteins and to form conjugates in which the protein and ferritin are bound by disulfide bonds. An electron-microscopic investigation of the negatively stained preparations of mitochondrial F1-ATPase, preincubated with modified ferritin, revealed such enzyme-ferritin conjugates. In case of modified ferritin, containing 360 mol SH-groups per mol protein, and F1-ATPase, pretreated with N-ethylmaleimide and then with dithiothreitol, conjugates were obtained in which ferritin molecules are bound to several (as many as four) of the six protein masses, comprising a bilayer molecule of the enzyme. Taking into consideration the biochemical data on the location of accessible SH-groups (only in alpha, gamma or epsilon subunits), it is inferred from the results obtained that one of the protein masses is a complex between beta subunit and at least one of the minor subunits located partially on the molecule's external side. This indicates the nonequivalence of different copies of the major subunits. Averaged images of the particles of the F1-F0 complex from bovine heart mitochondria and bacteria Micrococcus lysodeicticus were obtained. It was found that F0 component is bound to two adjacent protein masses of the F1-ATPase molecule. It is suggested that this binding may be due the nonequivalency of single-type major subunits.

Animals↗

PubMed2000

Evaluation of 24-color multifluor-fluorescence in-situ hybridization (M-FISH) karyotyping by comparison with reverse chromosome painting of the human breast cancer cell line T-47D.

Multifluor-fluorescence in-situ hybridization (M-FISH) chromosome paints for all the chromosomes in the human complement labeled with different combinations of fluorochromes is a recent technological development enabling assignment of chromosomal material to rearranged chromosomes. Little data is available on the accuracy and limitations of the approach to the analysis of complex karyotypes, which are characteristic of many malignant diseases. Here we compare M-FISH analysis of the breast-cancer-derived cell line T-47D with a previous analysis by reverse chromosome painting analysis of flow-sorted chromosomes from the same material. This demonstrated a high degree of concordance. It also illustrated the limitations of M-FISH analysis, including difficulties identifying small regions of chromosomal material and intrachromosomal rearrangements. Confirmation of selected aberrations using less-complex mixtures of painting probes and further definition of abnormalities using single copy markers may be required. The detailed karyotype description possible by M-FISH analysis contrasts with the definition in the original G-banding analysis. This and the level of concordance with reverse FISH painting supports the utility of the approach in the definition of complex karyotypes.

Breast Neoplasms↗

PubMed1995

Inhibition of human immunodeficiency virus type 1 integrase by a hydrophobic cation: the phenanthroline-cuprous complex.

The human immunodeficiency virus type 1 integrase (HIV-1 integrase) is required for integration of a double-stranded DNA copy of the viral RNA genome into a host chromosome and for HIV replication. We have examined the effects of 2:1 1,10-phenanthroline-cuprous complexes on purified HIV-1 integrase. Although the uncomplexed phenanthrolines are not active below 100 microM, four of the cuprous complexes (neocuproine, 4-phenyl neocuproine, 2,3,4,7,8,9-hexamethyl phenanthroline, and 2,3,4,7,8-pentamethyl phenanthroline) have a 50% inhibitory concentration (IC50) for integration ranging between 1 and 10 microM. Disintegration is also inhibited by these phenanthroline-cuprous complexes at slightly higher concentrations (between 10 and 40 microM). Dialysis experiments showed that the inhibition is reversible and kinetic analyses revealed that the mode of inhibition by these cuprous complexes appears to be noncompetitive with respect to the substrate DNA. Consistent with these findings, binding assays demonstrate that, although these complexes can inhibit binding to DNA at high concentrations, they do not inhibit binding of integrase to the DNA substrate at their IC50 values. Because these complexes do not bind to B-DNA below 50 microM, inhibition via binding to a specific region on the enzyme was examined. Using deletion mutants of integrase, it was determined that neither the amino-terminal (zinc finger) nor the carboxy-terminal (DNA-binding) integrase domain is required for inhibition by the phenanthroline-cuprous complexes. Therefore, inhibition via binding to the enzyme catalytic core or to the interface between the enzyme and a noncanonical DNA structure generated during the enzymatic reaction is the probable mechanism. These results suggest the utility of neocuproine-cuprous complexes in developing inhibitors of HIV-1 integrase as well as probes for drug-binding sites and enzymatic reaction mechanism.

Base Sequence↗

PubMed1997

Phosphorylation mutants of p53 show differential complex formation with putative dehydrogenase Tms1 of fission yeast.

The yeast tms1 gene was originally identified as a multi-copy suppressor of a lethal growth arrest caused by expression of a tumour mutant cDNA of p53 in fission yeast. The tms1 gene product (Tms1) was found to form stable complexes with p53 in yeast and in vitro; using purified recombinant proteins, the interaction was mapped to the C-terminal region of p53. This part is known to be modified by several protein kinases resulting in a transition of p53 from a latent to an activated state capable of transactivating various cellular genes involved in growth suppression or apoptosis. Since there is evidence for an evolutionary conservation of a Tms1-related protein in mammals, the effect of the phosphorylation status of the C-terminus of p53 on Tms1/p53 complex formation in vitro has been investigated. Whereas mutants changing the cdc2 phosphorylation site at position 315 of human p53 had only little effect on Tms1/p53 complex formation, we found that mutants involving the protein kinase CK2 site at position 392 showed a significantly decreased relative affinity for the Tms1 protein. The same result was obtained by using a C-terminal fragment of p53 which was phosphorylated by purified protein kinase CK2, suggesting that the complex formation of p53 with cellular C-terminal binding proteins like Tms1 impairs regulation by phosphorylation.

Binding Sites↗

PubMed1994

Isolation of the stable hexameric DnaK.DnaJ complex from Thermus thermophilus.

A DnaK homolog (T.DnaK) has been purified as a stable complex with a DnaJ homolog (T.DnaJ) from a thermophilic bacterium, Thermus thermophilus. This complex has an approximate molecular size of 300 kDa and appears to contain three copies of each of T.DnaK and T.DnaJ molecules. Consistently, trigonal ring structures with a diameter (trigonal apex-to-apex) of about 11 nm were observed with electron microscopy. The complex has no endogenously bound AT(D)P and is stable in the presence of Mg-AT(D)P. It possesses a weak ATPase activity and retains about 3 mol of ADP/mole of the complex when incubated with Mg-ATP. This complex is able to interact with the reduced carboxymethylated alpha-lactalbumin which we used as a model unfolded protein.

Adenosine Triphosphatases↗

PubMed1985

The precursor complex of Pf3 bacteriophage.

Filamentous bacteriophage infections give rise to intracellular filamentous precursor complexes composed of a circular single-stranded DNA molecule and on the order of 10(3) copies of a viral-encoded, single-stranded DNA binding protein. A protocol was developed for the purification of the precursor complex from Pf3 phage-infected Pseudomonas aeruginosa cells, and existing protocols for Ff and Pf1 complexes were amended by the introduction of a molecular sieving column step. The Pf3 precursor complex has an average contour length of 500 nm, which is shorter than that of the mature Pf3 virus. M/L (mass/length) values were obtained from turbidity measurements, from scanning-transmission electron microscopy, and from the total particle mass divided by its length. The average M/L obtained was 19,300 Da/nm which is close to that of the Pf3 virion. The complex has a nucleotide/subunit ratio of 6.0. The protein component of the precursor complex has less than 10% alpha-helicity, whereas the protein component of the virus is greater than 90% alpha-helical. The DNA structure in the precursors is very different from that in the virus, so that during virus assembly the DNA structure must change dramatically. The results for the Pf3 system, together with the available information for the Ff and Pf1 filamentous virus systems, indicate that different DNA-protein interactions and packing arrangements are involved in performing equivalent functions.

Bacteriophages↗

PubMed2001

47,XXX male: A clinical and molecular study.

We report a 53-year-old Japanese male with a 47,XXX karyotype. His clinical features included hypoplastic scrotal testes (4 ml bilaterally), normally formed small penis (3.8 cm), relatively poor pubic hair development (Tanner stage 3), gynecomastia, age-appropriate male height (159.1 cm), and mental retardation (verbal IQ of 56). Serum testosterone was markedly reduced (0.6 nmol/L). A needle biopsy showed severe testicular degeneration. FISH analysis revealed complex mosaicism consisting of (1) 47,XXX cells with a single copy of SRY (n = 177), two copies of SRY (n = 3), and no SRY (n = 1); (2) 46,XX cells with a single copy of SRY (n = 9) and no SRY (n = 3); (3) 45,X cells with no SRY (n = 5); and (4) 48,XXXX cells with a single copy of SRY (n = 1) and two copies of SRY (n = 1). PCR analysis showed the presence of Yp portion with the breakpoint between DYS264 and AMELY. Microsatellite analysis demonstrated three alleles for DMD and AR. X-inactivation analysis for the methylation status of the AR gene showed random inactivation of the three X chromosomes. The results suggest that this 47,XXX male has resulted from abnormal X-Y interchange during paternal meiosis and X-X nondisjunction during maternal meiosis. Complex mosaicism may be due to the age-related increase in mitotic nondisjunction which is prone to occur in rapidly dividing lymphocytes and to the presence of two randomly inactivated X chromosomes which may behave asynchronously during mitosis, and clinical features of this male would primarily be explained by the genetic information on the SRY (+) der(X) chromosome and his advanced age.

Adolescent↗

PubMed1996

Differential inhibition of HIV-1 preintegration complexes and purified integrase protein by small molecules.

To replicate, HIV-1 must integrate a cDNA copy of the viral RNA genome into a chromosome of the host. The integration system is a promising target for antiretroviral agents, but to date no clinically useful integration inhibitors have been identified. Previous screens for integrase inhibitors have assayed inhibition of reactions containing HIV-1 integrase purified from an Escherichia coli expression system. Here we compare action of inhibitors in vitro on purified integrase and on subviral preintegration complexes (PICs) isolated from lymphoid cells infected with HIV-1. We find that many inhibitors active against purified integrase are inactive against PICs. Using PIC assays as a primary screen, we have identified three new anthraquinone inhibitors active against PICs and also against purified integrase. We propose that PIC assays are the closest in vitro match to integration in vivo and, as such, are particularly appropriate for identifying promising integration inhibitors.

Anthraquinones↗

PubMed2003

Induction of specific T-helper and cytolytic responses to epitopes displayed on a virus-like protein scaffold derived from the pyruvate dehydrogenase multienzyme complex.

The icosahedral protein scaffold (1.5MDa) generated by self-assembly of the catalytic domains of the dihydrolipoyl acetyltransferase core of the pyruvate dehydrogenase multienzyme complex from Bacillus stearothermophilus has been engineered to display 60 copies of one or more peptide epitopes on a single molecule (E2DISP). An E2DISP scaffold displaying pep23, a 15-residue B- and T-helper epitope from the reverse transcriptase of HIV-1, was able to induce a pep23-specific T-helper response in cell lines in vitro. The same scaffold displaying both pep23 and peptide RT2, a nine-residue CTL epitope from HIV-1 reverse transcriptase, was able to prime an RT2-specific CD8(+) T-cell response in human cell lines in vitro and in HLA-A2 transgenic mice in vivo. This was accompanied by a humoral antibody response specific for E2DISP-presented epitopes. Thus, the icosahedral acetyltransferase core constitutes a simple and flexible scaffold for multiple epitope display with access to both cellular and humoral immune response pathways.

Acetyltransferases↗

PubMed2002

Discrimination of Mycobacterium tuberculosis complex bacteria using novel VNTR-PCR targets.

The lack of a convenient high-resolution strain-typing method has hampered the application of molecular epidemiology to the surveillance of bacteria of the Mycobacterium tuberculosis complex, particularly the monitoring of strains of Mycobacterium bovis. With the recent availability of genome sequences for strains of the M. tuberculosis complex, novel PCR-based M. tuberculosis-typing methods have been developed, which target the variable-number tandem repeats (VNTRs) of minisatellite-like mycobacterial interspersed repetitive units (MIRUs), or exact tandem repeats (ETRs). This paper describes the identification of seven VNTR loci in M. tuberculosis H37Rv, the copy number of which varies in other strains of the M. tuberculosis complex. Six of these VNTRs were applied to a panel of 100 different M. bovis isolates, and their discrimination and correlation with spoligotyping and an established set of ETRs were assessed. The number of alleles varied from three to seven at the novel VNTR loci, which differed markedly in their discrimination index. There was positive correlation between spoligotyping, ETR- and VNTR-typing. VNTR-PCR discriminates well between M. bovis strains. Thirty-three allele profiles were identified by the novel VNTRs, 22 for the ETRs and 29 for spoligotyping. When VNTR- and ETR-typing results were combined, a total of 51 different profiles were identified. Digital nomenclature and databasing were intuitive. VNTRs were located both in intergenic regions and annotated ORFs, including PPE (novel glycine-asparigine-rich) proteins, a proposed source of antigenic variation, where VNTRs potentially code repeating amino acid motifs. VNTR-PCR is a valuable tool for strain typing and for the study of the global molecular epidemiology of the M. tuberculosis complex. The novel VNTR targets identified in this study should additionally increase the power of this approach.

Alleles↗

PubMed1998

Complex familial rearrangement of chromosome 9p24.3 detected by FISH.

We describe a newborn male with minor facial anomalies, pyloric stenosis, and a chromosome rearrangement that involves deletion and addition of material at 9p24.3. Routine studies showed a 46, XY, add (9) (p24) karyotype. Fluorescence in situ hybridization (FISH) with two different whole chromosome probes for chromosome 9 failed to identify whether the additional material was derived from that chromosome. FISH with single copy YAC probes from 9p24 (D9S1858, D9S1813 and D9S54) showed a more complex rearrangement involving a deletion at D9S1858 but not at D9S1813 or D9S54. Parental chromosome studies demonstrated an apparently identical 9p abnormality in the patient's mother. This report describes a familial chromosome rearrangement in an abnormal child and his normal mother and demonstrates the use and limitations of FISH in characterizing chromosomal abnormalities.

Abnormalities, Multiple↗

PubMed2001

A novel carbohydrate-binding protein is a component of the plant cell wall-degrading complex of Piromyces equi.

The recycling of photosynthetically fixed carbon by the action of microbial plant cell wall hydrolases is a fundamental biological process that is integral to one of the major geochemical cycles and, in addition, has considerable industrial potential. Enzyme systems that attack the plant cell wall contain noncatalytic carbohydrate-binding modules (CBMs) that mediate attachment to this composite structure and play a pivotal role in maximizing the hydrolytic process. Anaerobic fungi that colonize herbivores are the most efficient plant cell wall degraders known, and this activity is vested in a high molecular weight complex that binds tightly to the plant cell wall. To investigate whether plant cell wall attachment is mediated by noncatalytic proteins, a cDNA library of the anaerobic fungus Piromyces equi was screened for sequences that encode noncatalytic proteins that are components of the cellulase-hemicellulase complex. A 1.6-kilobase cDNA was isolated encoding a protein of 479 amino acids with a M(r) of 52548 designated NCP1. The mature protein had a modular architecture comprising three copies of the noncatalytic dockerin module that targets anaerobic fungal proteins to the cellulase-hemicellulase complex. The two C-terminal modules of NCP1, CBM29-1 and CBM29-2, respectively, exhibit 33% sequence identity with each other but have no homologues in protein data bases. A truncated form of NCP1 comprising CBM29-1 and CBM29-2 (CBM29-1-2) and each of the two individual copies of CBM29 bind primarily to mannan, cellulose, and glucomannan, displaying the highest affinity for the latter polysaccharide. CBM29-1-2 exhibits 4-45-fold higher affinity than either CBM29-1 or CBM29-2 for the various ligands, indicating that the two modules, when covalently linked, act in synergy to bind to an array of different polysaccharides. This paper provides the first report of a CBM-containing protein from an anaerobic fungal cellulase-hemicellulase complex. The two CBMs constitute a novel CBM family designated CBM29 whose members exhibit unusually wide ligand specificity. We propose, therefore, that NCP1 plays a role in sequestering the fungal enzyme complex onto the plant cell wall.

Amino Acid Sequence↗

PubMed2006

Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype.

Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about gamma-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in gamma-secretase cleavage activity towards one of its best-known substrates, the amyloid-beta precursor protein APP. We conclude that the low levels of Aph-1b mRNA and gamma-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

Animals↗