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At least 19 recordsLinked to original sources
PubMed1987

Subdivisions and connections of inferior temporal cortex in owl monkeys.

Patterns of cortical connections and differences in architectonic appearance were used to subdivide inferior temporal cortex of owl monkeys into four main regions. These regions were named by location: ITC (the caudal subdivision of inferior temporal cortex), ITR (the rostral subdivision of inferior temporal cortex), ITP (the polar subdivision of inferior temporal cortex), and ITM (the medial subdivision of inferior temporal cortex). Two of these regions may contain further subdivisions--ITC, separate dorsal and ventral areas, and ITM, medial and lateral areas. The most caudal subdivision, ITC, was defined in an earlier report (Weller and Kaas: J. Comp. Neurol. 234:35-59, '85) as the projection zone of the dorsolateral visual area (DL). ITC occupies roughly the caudal half of the architectonic zone temporal area E (TE) (after von Bonin and Bailey: The Neocortex of Macaca mulatta. Urbana: University of Illinois Press, '47). TE is characterized by a dense, broad layer IV of granule cells and a dark inner band of myelination. Injections of 3H-proline in ITC demonstrated major projections to a more rostral division of the temporal lobe, ITR. Other projections were to the frontal eye field (FEF), a more ventral region of frontal cortex (FV), and a medial division of inferior temporal cortex, ITM, on the ventral surface of the temporal lobe. Feedback projections of ITC were to DL and adjoining temporal-parietal cortex (TP), while interhemispheric projections were to ITC and ITR. Connections between dorsal and ventral ITC, together with earlier evidence for two projection zones of DL in ITC (Weller and Kaas: ibid., '85), suggest that dorsal and ventral sectors of ITC are separate visual areas. The rostral division of inferior temporal cortex, ITR, was defined as the projection zone of ITC. ITR occupied the rostral half of the architectonic region TE. Slight differences in cortical architecture between ITC and ITR were noted, but an architectonic border between the two fields could not be reliably distinguished. Injections in ITR demonstrated projections to the rostral pole of temporal cortex, ITP, feedback projections to ITC, and inputs to FEF, FV, dorsomedial frontal cortex, and the rostroventral superior temporal gyrus. Interhemispheric projections were to ITR and ITP. The projections of ITR to the rostral pole defined ITP. ITP has broad, less distinct layers of cortex and appears to correspond to temporal area G (TG) of von Bonin and Bailey (ibid., '47). The only known input to ITP is from ITR, and its projections have not yet been determined.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1990

Treatment of isolated testicular relapse in childhood acute lymphoblastic leukemia: an Italian multicenter study. Associazione Italiana Ematologia ed Oncologia Pediatrica.

Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARA-C), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Patients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice.

Although isotretinoin (ITR) has been suggested to cause malformations via cytopathic effects on embryonic cells, the molecular mechanisms of ITR cytotoxicity in teratogenesis are not clear. Since ITR undergoes metabolism by prostaglandin synthase to a potentially cytotoxic peroxyl free radical, the possible role of prostaglandin synthase metabolism as a modulator of ITR teratogenicity was evaluated. Craniofacial and limb abnormalities were noted in fetuses on day 18.5 of gestation following administration of ITR to pregnant CD-1 mice in a three dose regimen of 100 mg/kg at 4 hr intervals on day 10.5 of gestation (plug day = day 0.5 of gestation). Mice were also treated with acetylsalicylic acid (ASA), an irreversible inhibitor of the cyclooxygenase component of prostaglandin synthase, at doses of 20 and 60 mg/kg body weight 2 hr prior to each ITR dose. ASA pretreatment of mice receiving ITR treatment showed a dose-dependent decrease in the overall incidence of malformations, number of defects per fetus, and the incidence of specific craniofacial and limb defects. Equivalent doses of ASA given to control mice did not cause malformations or alter the incidence of resorptions. These results demonstrate that ASA is able to ameliorate the teratogenic effects of ITR observed in fetal mice near term and indicate that prostaglandin metabolism could play a mechanistic role in ITR teratogenicity.

Animals↗
PubMed1991

Redundant elements in the adenovirus type 5 inverted terminal repeat promote bidirectional transcription in vitro and are important for virus growth in vivo.

The adenovirus inverted terminal repeat (ITR) contains a number of cis-acting elements that are involved in the initiation of viral DNA replication, as well as multiple binding motifs for the cellular transcription factors SP1 and ATF. In this study, we utilized a Hela cell transcription extract to demonstrate that the adenovirus type 5 ITR promotes bidirectional transcription in vitro. Primer extension analyses demonstrated that the ITR directed transcription at initiation sites both within the terminal repeat and at fixed distances outside of the ITR. The ITR also strongly stimulated transcription at the early region 1A (E1A) initiation site when it was situated immediately upstream of the E1A TATA box region. Deletion and point mutational analyses demonstrated that two distinct cis-acting elements were involved in these ITR-dependent transcriptional activities in vitro. Cellular transcription factors SP1 and ATF were previously shown to bind to these two regions. Analysis of viral mutants in vivo demonstrated that the NFIII/OCT-1 binding site and a conserved ATF motif were important for efficient viral growth. Regulatory elements in the ITR flanking region were found to functionally substitute for these sites.

Adenoviruses, Human↗
PubMed2026

Systematic mapping of insertion-tolerant regions enables capsid engineering of an infectious RNA phage.

RNA phages are attractive platforms for the design of programmable bioparticles, but their development has been constrained by limited knowledge of genomic sites that can tolerate sequence insertion. Here, we combined MuA transposase-mediated in vitro insertion mutagenesis with our established reverse genetics systems to systematically identify insertion-tolerant regions (ITRs) in the RNA phages MS2 and PP7. Screening of 4,555 MS2 and 2,228 PP7 random insertion clones identified 29 and 26 non-redundant ITRs, respectively. We further analyzed and compared these ITRs in the context of RNA genome organization and virion architecture. Both phages contained ITRs within the maturation protein, whereas only PP7 tolerated insertions within the coat protein (CP). On the basis of structural location and plaque-forming capacity, an ITR situated between Gly74 and Glu75 (GGC^GAG) in the PP7 CP was selected for further study. Infectious phage particles generated from complementary DNA clones retained the 15-bp insertion at both the RNA and protein levels. Engineered PP7 phages carrying an Arg-Gly-Asp motif inserted into the CP at this ITR displayed enhanced in vivo clearance in a Drosophila model, despite having in vitro stability comparable to that of the wild type. These findings provide the first example of CP engineering in an infectious RNA phage and establish a framework for engineering RNA phages for biological and biotechnological applications.IMPORTANCEA major obstacle to developing RNA phages as synthetic biology platforms is the lack of design principles for genomic insertion. Here, we address this limitation by establishing a mutagenesis-and-recovery workflow that systematically identifies insertion-tolerant regions (ITRs) in the RNA phages MS2 and PP7. The resulting maps reveal distinct structural constraints in the two phages and enable rational engineering of a peptide-display site in the PP7 capsid. Using this approach, we generated an engineered infectious phage with a modified capsid, thereby providing the first demonstration of capsid engineering in an infectious RNA phage, to our knowledge. This study lays the groundwork for the rational design of live RNA phage virions as tractable and engineerable scaffolds for future biological and biotechnological applications.

Animals↗
PubMed1986

Analysis of Tn3 sequences required for transposition and immunity.

Tn3 is a 5-kb transposon (Tn) with 38-bp inverted terminal repeats (ITR). The two 38-bp terminal sequences are required in cis for Tn3 transposition. In this study, the role of the ITR in Tn3 transposition has been further dissected by the use of various mini-Tn3 Tn's. The transposition frequency of these mini-Tn's demonstrate that Tn3 contains no sequence other than the ITR sequences that are necessary for the first step in transposition; the two terminal repeats must be oriented as ITR for transposition to occur; the outside 34 bp of the ITR are required for transposition; and reducing the distance between the terminal sequences does not affect transposition frequency. Moreover, mutant copies of the ITR sequences that cannot function in transposition do not confer transposition immunity.

Base Composition↗
PubMed2026

Modified Plasmids and Inverted Terminal Repeats Enhance Adeno-Associated Virus Production and Performance.

Recombinant adeno-associated virus (rAAV) is a preferred vector in gene therapy, although high production costs inhibit widespread adoption. The most common approach for rAAV production involves transfection of HEK293 cells with three plasmids: pTransgene, pRep/Cap and pHelper. Producing sufficient amounts of these plasmids accounts for up to 40% of total batch costs. Initially, this work aimed to increase plasmid yields by replacing the backbones. While this approach increased pHelper yields, pRep/Cap and pTransgene yields were unaffected. A possible reason was identified: pTransgene contains inverted terminal repeat (ITR) sequences that are essential for rAAV production. ITRs have strong secondary structures (including hairpin loops termed B and C arms) that likely interfere with plasmid production. Therefore, targeted deletions were performed within the ITRs. Partial deletions in both the B and C arms of the ITR were most beneficial, as both plasmid yield and transgene expression increased. Importantly, partial deletions did not reduce rAAV yield, as had been previously observed when the B and C arms were fully deleted. In summary, we report a 140% increase in pHelper plasmid production, while the most successful ITR variant increased pTransgene plasmid yields by 57% and transgene expression by 28%, without reducing rAAV yields or transduction efficiency.

Humans↗
PubMed1992

Cortical connections of subdivisions of inferior temporal cortex in squirrel monkeys.

Patterns of cortical connections and architectonics were used to determine subdivisions of inferior temporal (IT) cortex of squirrel monkeys. Single or multiple injections of the tracers wheat germ agglutinin-horseradish peroxidase, Fast Blue, Diamidino Yellow, Fluoro-Gold, and 3H-amino acids were placed into IT cortex. Most injections were placed in caudal IT cortex in the region previously shown to receive input from the caudal subdivision of the Dorsolateral Area, DLC; additional injections were placed in more rostral IT cortex. The results indicate the presence of two major regions: a caudal region, ITC, and a rostral region, ITR. An intermediate region of cortex along the ITC-ITR border that displays some connections of ITC and some connections of ITR may be another area. ITC contains a more myelinated dorsal area, ITCd, and a larger ventral area, ITCv. Both ITCd and ITCv receive a major projection from DLC; additional input from DLR, MT, and VII; and send strong projections to ITR, the lateral bank of the superior temporal sulcus, and dorsolateral prefrontal cortex. Only ITCd has strong connections with DLR and cortex in the depths of the superior temporal sulcus, and only ITCv has connections with lateral orbital cortex. The overall pattern of connections between ITC and DLC suggests that ITC has a crude topographic organization, with dorsal cortex representing the lower field and ventral cortex representing the upper field. ITR differs from ITC by receiving little if any input from DLC; projecting to inferior temporal polar cortex, the rostral Sylvian fissure, and medial orbital cortex; and having a less distinct layer IV. Comparison of subdivisions of inferior temporal cortex defined in the present study in squirrel monkeys and those reported in other primates suggests that ITC of squirrel monkeys may correspond to area TEO of macaque monkeys.

Animals↗
PubMed1986

Teratogen update: vitamin A congeners.

Despite animal vitamin A congener teratogenicity in animal studies since 1954, striking human findings only arose in 1983 following isotretinoin (ITR) marketing for oral treatment of severe acne. By November 1985, 44 outcomes with central nervous system (CNS), cardioaortic (CV), microtia, facial palsy, micrognathia, cleft palate, and/or thymic aplasia defects, and 33 spontaneous abortions have been reported. The critical period for exposure appears to be two to five weeks postconception, although this is clinically inexact. ITR half life is less than a day, although a teratogenic metabolite, 4-oxo-isoretinoin, has a half life of several days. Seven defect outcomes and one stillbirth have been reported with another congener, etretinate (ETR), used for psoriasis. Three of these had meningomyeloceles. Half life of several months makes levels cumulative. Only one additional defect, which may have occurred by chance, is reported with use stopped before conception (4 months). Other discontinuations 1 to 6 months before conception had 11 normal outcomes and two spontaneous abortions. ITR and ETR dose ranged from 0.5 to 1.5 mg/kg. Normal outcomes are reported both with ITR and ETR, but some of these appear not to have been exposed during the critical period. Less striking defects, abortions, and normal outcomes are less well reported. Because vitamin A analogs are therapeutically important and unplanned outcome not always avoidable, further animal research is needed for better risk/benefits. Megadose vitamin A (retinol) use is widespread, but experience poorly observed. Eighteen suspicious birth defect outcomes have been reported from pregnancies with high dose exposure. Twelve had findings similar to those seen in animals and in human retinoid syndromes, e.g., CNS, CV, microtia, and clefts. Epidemiological controls are lacking to establish human teratogenicity, but based on animal studies and experience with ITR and ETR, avoiding long term megadose Vitamin A use in fertile women is warranted.

Abnormalities, Drug-Induced↗
PubMed1990

Sequence analysis of the inverted terminal repetition in the genome of the parapoxvirus, orf virus.

Two BamHI fragments from the right-hand terminal region of the orf virus genome have been sequenced. The bulk of the inverted terminal repetition (ITR) sequence is contained within these fragments and makes up 3388 bp of the 4425-bp sequence reported. The overall base composition of the larger sequence is 59.4% G + C and of the ITR, 60.2% G + C. An extremely G/C-rich (83.2%) block of sequence was found spanning the ITR/unique sequence junction. The bulk of the ITR could be divided into three blocks of directly repeated sequences. One block begins about 250 nucleotides from the terminus and is a direct repeat 15 bp long, repeated 14 times. The other blocks contain seven sequence sets ranging from 16 to 36 nucleotides which are repeated 2 to 4 times, interspersed with one another, interrelated in sequence, and sometimes separated by unique sequence. Eight open reading frames (ORFs), each with the potential to code for polypeptides of 50 residues or more, were identified. Three were found within the ITR, four spanned the ITR/unique sequence junction and one was found outside the ITR. A search for putative poxvirus transcriptional control signals indicated that three of the eight ORFs are likely to be transcribed early, all in the same direction toward the right end of the genome. Sequences of the type T(A)3-5T were found only twice in the sequence and only one preceded an ORF.

Amino Acid Sequence↗
PubMed1987

Phylogenetic relationships between adenoviruses as inferred from nucleotide sequences of inverted terminal repeats.

The nucleotide (nt) sequences of inverted terminal repeats (ITR) from human adenovirus (Ad) 19, bovine Ad1 (BAd1), bovine Ad3 (BAd3), canine Ad2 (CAd2) and an avian Ad, EDS-76, were determined. The length of the ITR sequence was 160 bp in Ad19, 159 bp in BAd1, 195 bp in BAd3, 196 bp in CAd2 and 52 bp in EDS-76. CAd2 had the longest ITR among the examined Ads, BAd3 the second longest, and EDS-76 had the shortest ITR. A TAAT sequence located between the 10th and 13th nt counted from the ends was conserved in all Ads examined so far. To determine phylogenetic relationships among human and animal Ads, sequences of their ITRs were compared, and a phylogenetic tree was constructed by using the maximum-likelihood method. It is the method involving statistical analysis of computing the probability of a particular set of sequences on a given tree and maximizing this probability over all evolutionary trees [Felsenstein, J. Mol. Evol. 17 (1981) 368-376]. From these analyses, it was found that members belonging to the same human Ad subgenus are related closely to each other, whereas representatives of different human subgenera are distributed rather divergently among animal Ads.

Adenoviridae↗
PubMed1989

Characterization of the simian adenovirus type 30 inverted terminal repeat.

The presence of an inverted terminal repeat (ITR), which plays an important role in the initiation of DNA replication, is one of the characteristic properties of adenoviruses (Ads). We have established the nucleotide (nt) sequences for the ITR of simian adenovirus type 30 (SV30), a subgroup-III oncogenic virus. This repeat consists of 185 nt, representing the longest ITR found in an Ad so far. It contains multiple copies of internal repeats, as well as the consensus sequences of the putative binding sites for replication and transcription factors. The conserved features of the known ITRs are also found in SV30. Interestingly, the ITR of SV30 is more closely related to that of Ad5 (human), than to that of SA7 (simian).

Adenoviridae↗
PubMed1990

Chagas' disease. Immunotoxin inhibition of Trypanosoma cruzi release from infected host cells in vitro.

Virulent tissue culture-derived Trypanosoma cruzi trypomastigotes were readily killed by immune IgG-ricin A chain conjugates (ITR) in vitro. Forty micrograms of ITR immobilized 10(6) trypomastigotes after 48 hours of incubation at 37 degrees C. ITR showed antibody specificity and 125I-labeled anti-T. cruzi IgG bound to parasitized host cells 9-fold more than to nonparasitized host cells. The degree of specificity was evaluated further in experiments in which 10 micrograms of ITR showed 78% inhibition of [3H]thymidine incorporation by T. cruzi. In contrast, nonimmune IgG-ricin A chain conjugate neither immobilized nor inhibited [3H]thymidine incorporation by the parasite. Furthermore, 20 micrograms of ITR significantly inhibited T. cruzi trypomastigote release from infected host cells and thus prevented reinfection of other cells in vitro.

Animals↗
PubMed1989

Effect of immunotoxins against Trypanosoma cruzi.

Immunotoxins were constructed with IgG antibodies against Trypanosoma cruzi surface antigens by hybridization with abrin (ITA) and ricin (ITR) A chains. The biological activity of the hybrid macromolecules was tested on the parasite forms. Motility of parasite forms was lost in vitro after incubation with ITR. In general, killing of the parasite with ITR was more efficient than with ITA. Inhibition of protein synthesis after incubation with either ITR or ITA, measured by 3H-leucine incorporation, confirmed the parasite immobilization experiments. The lethal effect was potentiated when the immunotoxins were used in the presence of 2.5 mM ammonium chloride. T. cruzi antibodies specific to cell surface antigens are excellent drug carriers that can be delivered to the target cell. However, ITR and ITA did not reduce parasitemia or increase survival of mice infected with T. cruzi.

Abrin↗
PubMed1978

Serum activity inhibiting specific simian virus 40-induced transplantation resistance and its correlation with primary SV40 tumors appearance in hamsters.

Using the modified technique of transplantation test, ITR serum activity was found in most (14 out of 21) individual hamster sera obtained during the latent period of primary SV40 carcinogenesis (60 days after virus infection when newborn). On the other hand, as a rule, no ITR activity was observed in the sera of the same hamsters after tumor appearance and during their growth. ITR activity rapidly disappeared from sera of hamsters neonatally infected with SV40 after their successful immunization with the same virus during the latent period. There appears to be a correlation between the presence of ITR serum factor during the latent period and the subsequent primary SV40 tumor appearance in hamsters.

Animals↗
PubMed1987

Multiple reiteration of a 40-bp nucleotide sequence in the inverted terminal repeat of the genome of a canine adenovirus.

The DNA of a vaccine strain of canine adenovirus type 1 [ICHV vaccine; Connaught Laboratories, Ltd.; CAV-1(CLL)] has been cloned in plasmid pAT153 in the form of subgenomic BamHI digestion fragments. Analysis of the nucleotide sequences of cloned terminal fragments has revealed an inverted terminal repeat (ITR) with a minimum length of 198 nucleotides, including a tandem reiteration of the 40-bp nucleotide sequence from positions 14 to 53. The ITRs had the 5'-CATCATCAAT ... sequence typical of adenoviruses and the highly conserved sequence ATAATATAC (nucleotides 9-17) of human strains. Additionally, one BamHI A clone (left terminus) contained three sequential copies of the 40-bp sequence, and two BamHI C clones (right terminus) contained at least seven. These did not appear to be artifacts of cloning, since evidence was obtained that the multiple reiterations also occurred in DNA isolated from intact virus. By analogy with human adenoviruses, the repetitive sequence in the CAV-1(CLL) genome encompasses the entire nuclear factor I (NFI) binding site of the origin of DNA replication. Additionally, the 40-bp nucleotide sequence was found to contain the sequence AGG(N)4GCCTAA (nucleotides 27-39), which closely resembles the concensus sequence of the human adenovirus NFI binding site [TGG(N)6-7GCCAA; nucleotides 25-38]. It appears, therefore, that the Connaught CAV-1 vaccine contains reiterated copies of an essential part of the adenoviral origin of DNA replication. A mechanism is proposed for the generation of multiple reiterations of sequences in the right ITR, given an initial single tandem repeat in the left ITR.

Adenoviridae↗
PubMed1985

Inverted terminal repeats and terminal proteins of the genomes of pneumococcal phages.

The nucleotide (nt) sequence at the ends of the genomes of the Streptococcus pneumoniae phages Cp-5 and Cp-7 has been determined and compared with the corresponding sequence of phage Cp-1. The genomes of phages Cp-5 and Cp-7 have inverted terminal repeats (ITRs) 343 and 347 bp long, respectively. In Cp-1 DNA the ITR is 236 bp long and the following 116 bp are 93% homologous. Some regions within the ITRs are conserved in the three genomes although the complete sequence of the ITRs is no more conserved than the rest of their genomes. The chromatographic behavior of their tryptic peptides suggests that the terminal proteins (TPs) of at least two of the phages are similar and that the TPs of the three pneumococcal phages differ markedly from that of the Bacillus subtilis phage psi 29.

Bacteriophages↗
PubMed2024

Enhanced transgene expression from single-stranded AAV vectors in human cells in vitro and in murine hepatocytes in vivo.

We identified that distal 10 nucleotides in the D-sequence in AAV2 inverted terminal repeat (ITR) share partial sequence homology to 1/2 binding site of glucocorticoid receptor-binding element (GRE). Here, we describe that (1) purified GR binds to AAV2 D-sequence, and the D-sequence competes with GR binding to its cognate binding site; (2) dexamethasone-mediated activation of GR pathway significantly increases the transduction efficiency of AAV2 vectors in human cells; (3) human osteosarcoma cells, U2OS, which lack expression of GR, are poorly transduced by AAV2 vectors, but stable transfection with a GR expression plasmid restores vector-mediated transgene expression; (4) replacement of the distal 10 nucleotides in the D-sequence of the AAV2 ITR with a full-length GRE consensus sequence significantly enhances transgene expression in human cells in vitro and in murine hepatocytes in vivo; and (5) none of the ITRs in AAV1, AAV3, AAV4, AAV5, and AAV6 genomes contains the GRE 1/2 binding site, and insertion of a full-length GRE consensus sequence in the AAV6-ITR also significantly enhances transgene expression from AAV6 vectors, both in vitro and in vivo. These novel vectors, termed generation Y AAV vectors, which are serotype, transgene, or promoter agnostic, should be useful in human gene therapy.

AAV vectors↗