Strong Evidence for

The boundaries of the chart of nuclides contain exotic isotopes that possess extreme proton-to-neutron asymmetries. Here we report on strong evidence of ^{9}N, one of the most exotic proton-rich isotopes where more than one half of its constitute nucleons are unbound. With seven protons and two neutrons, this extremely proton-rich system would represent the first-known example of a ground-state five-proton emitter. The invariant-mass spectrum of its decay products can be fit with two peaks whose energies are consistent with the theoretical predictions of an open-quantum-system approach; however, we cannot rule out the possibility that only a single resonancelike peak is present in the spectrum.

Dissipative Reactions with Intermediate-Energy Beams: A Novel Approach to Populate Complex-Structure States in Rare Isotopes.

A novel pathway for the formation of multiparticle-multihole excited states in rare isotopes is reported from highly energy- and momentum-dissipative inelastic-scattering events measured in reactions of an intermediate-energy beam of ^{38}Ca on a Be target. The negative-parity, complex-structure final states in ^{38}Ca are observed following the in-beam γ-ray spectroscopy of events in the ^{9}Be(^{38}Ca,^{38}Ca+γ)X reaction in which the scattered projectile loses longitudinal momentum of order Δp_{||}=700 MeV/c. The characteristics of the observed final states are discussed and found to be consistent with the formation of excited states involving the rearrangement of multiple nucleons in a single, highly energetic projectile-target collision. Unlike the far-less-dissipative, surface-grazing reactions usually exploited for the in-beam γ-ray spectroscopy of rare isotopes, these more energetic collisions appear to offer a practical pathway to nuclear-structure studies of more complex multiparticle configurations in rare isotopes-final states conventionally thought to be out of reach with high-luminosity fast-beam-induced reactions.

Observation of the Exotic Isotope

A ^{13}F resonance was observed following a charge-exchange reaction between a fast ^{13}O beam and a ^{9}Be target. The resonance was found in the invariant-mass distribution of 3p+^{10}C events and probably corresponds to a 5/2^{+} excited state. The ground state was also expected to be populated, but was not resolved from the background. The observed level decays via initial proton emissions to both the ground and first 2^{+} state of ^{12}O, which subsequently undergo 2p decay. In addition, there may also be a significant proton decay branch to the second 2^{+} level in ^{12}O. The wave function associated with the observed level may be collectivized due to coupling to the continuum as is it located just above the threshold for proton decay to the 2_{2}^{+} state of ^{12}O.

First Observation of the Four-Proton Unbound Nucleus

^{18}Mg was observed, for the first time, by the invariant-mass reconstruction of ^{14}O+4p events. The ground-state decay energy and width are E_{T}=4.865(34) MeV and Γ=115(100) keV, respectively. The observed momentum correlations between the five particles are consistent with two sequential steps of prompt 2p decay passing through the ground state of ^{16}Ne. The invariant-mass spectrum also provides evidence for an excited state at an excitation energy of 1.84(14) MeV, which is likely the first excited 2^{+} state. As this energy exceeds that for the 2^{+} state in ^{20}Mg, this observation provides an argument for the demise of the N=8 shell closure in nuclei far from stability. However, in open systems this classical argument for shell strength is compromised by Thomas-Ehrman shifts.

Shape Changes in the N=28 Island of Inversion: Collective Structures Built on Configuration-Coexisting States in

The neutron-rich nuclei in the N=28 island of inversion have attracted considerable experimental and theoretical attention, providing great insight into the evolution of shell structure and nuclear shape in exotic nuclei. In this work, for the first time, quadrupole collectivity is assessed simultaneously on top of the 3/2^{-} ground state and the 7/2^{-} shape-coexisting isomer of ^{43}S, putting the unique interpretation of shape and configuration coexistence at N=27 and 28 in the sulfur isotopic chain to the test. From an analysis of the electromagnetic transition strengths and quadrupole moments predicted within the shell model, it is shown that the onset of shape coexistence and the emergence of a simple collective structure appear suddenly in ^{43}S with no indication of such patterns in the N=27 isotone ^{45}Ar.

First Observation of Unbound

The structure of the extremely proton-rich nucleus _{8}^{11}O_{3}, the mirror of the two-neutron halo nucleus _{3}^{11}Li_{8}, has been studied experimentally for the first time. Following two-neutron knockout reactions with a ^{13}O beam, the ^{11}O decay products were detected after two-proton emission and used to construct an invariant-mass spectrum. A broad peak of width ∼3.4 MeV was observed. Within the Gamow coupled-channel approach, it was concluded that this peak is a multiplet with contributions from the four lowest ^{11}O resonant states: J^{π}=3/2_{1}^{-}, 3/2_{2}^{-}, 5/2_{1}^{+}, and 5/2_{2}^{+}. The widths and configurations of these states show strong, nonmonotonic dependencies on the depth of the p-^{9}C potential. This unusual behavior is due to the presence of a broad threshold resonant state in ^{10}N, which is an analog of the virtual state in ^{10}Li in the presence of the Coulomb potential. After optimizing the model to the data, only a moderate isospin asymmetry between ground states of ^{11}O and ^{11}Li was found.

Large Longitudinal Spin Alignment of Excited Projectiles in Intermediate Energy Inelastic Scattering.

We study the sequential breakup of E/A=24.0 MeV ^{7}Li projectiles excited through inelastic interactions with C, Be, and Al target nuclei. For peripheral events that do not excite the target, we find very large spin alignment of the excited ^{7}Li projectiles longitudinal to the beam axis. This spin alignment is independent of the target used, and we propose a simple alignment mechanism that arises from an angular-momentum-excitation-energy mismatch. This mechanism is independent of the potential used for scattering and should be present in many scattering experiments.

Observation of long-range three-body coulomb effects in the decay of (16)Ne.

The interaction of an E/A=57.6-MeV ^{17}Ne beam with a Be target is used to populate levels in ^{16}Ne following neutron knockout reactions. The decay of ^{16}Ne states into the three-body ^{14}O+p+p continuum is observed in the High Resolution Array (HiRA). For the first time for a 2p emitter, correlations between the momenta of the three decay products are measured with sufficient resolution and statistics to allow for an unambiguous demonstration of their dependence on the long-range nature of the Coulomb interaction. Contrary to previous measurements, our measured limit Γ<80 keV for the intrinsic decay width of the ground state is not in contradiction to the small values (of the order of keV) predicted theoretically.

Beam particle identification and tagging of incompletely stripped heavy beams with HEIST.

A challenge preventing successful inverse kinematics measurements with heavy nuclei that are not fully stripped is identifying and tagging the beam particles. For this purpose, the HEavy ISotope Tagger (HEIST) has been developed. HEIST utilizes two micro-channel plate timing detectors to measure the time-of-flight, a multi-sampling ion chamber to measure energy loss, and a high-purity germanium detector to identify isomer decays and calibrate the isotope identification system. HEIST has successfully identified 198Pb and other nearby nuclei at energies of about 75 MeV/A. In the experiment discussed, a typical cut containing 89% of all 198Pb80+ in the beam had a purity of 86%. We examine the issues of charge state contamination. The observed charge state populations of these ions are presented and, using an adjusted beam energy, are well described by the charge state model GLOBAL.

Identification of differential methylation of the WT1 antisense regulatory region and relaxation of imprinting in Wilms' tumor.

Wilms' tumor (WT) is associated with loss of heterozygosity at chromosome 11p13, the site of the Wilms' tumor suppressor gene, WT1. Although the preferential loss of maternal alleles suggested that differential allelic expression of WT1 might occur, this has not been evident in normal fetal tissues or WTs. In this study, we show that the WT1 antisense regulatory region is differentially methylated, with Southern blot analysis of four loss of heterozygosity-negative WTs and their corresponding normal kidneys indicating that allelic methylation is lost in WTs. Reverse transcription-PCR expression analysis correlates methylation with monoallelic expression of the antisense WT1 transcript (WT1-AS) in normal kidney. However, WTs display hypomethylation and biallelic expression of WT1-AS. Our findings are consistent with imprinting of WT1-AS in normal kidney and the relaxation of imprinting in Wilms' tumorigenesis. This identifies the WT1 antisense regulatory region in intron 1 as a primary site for epigenetic deregulation at chromosome 11p13 in WTs.

Identification of an antisense WT1 promoter in intron 1: implications for WT1 gene regulation.

Expression of the Wilms' tumour suppressor gene, WT1, is tightly regulated during nephrogenesis, and loss of function of its gene product correlates with malignancy. By using luciferase reporter gene constructs containing DNA sequences from the first intron of the WT1 gene, we have identified an antisense WT1 promoter operational in the opposite direction relative to the 5' promoter. Transcription directed by the promoter is negatively regulated by upstream elements, but is activated by expression of WT1. This effect of WT1 is reciprocal to that observed on the 5' promoter, suggesting that antisense promoter activity is involved in WT1 gene regulation. By mimicking expression of the transcript regulated by the antisense promoter, we demonstrate that cellular levels of WT1 can be effectively down-regulated by antisense mRNA complementary to sequences in the first exon of WT1.

Inactivation of the remaining allele of the WT1 gene in a Wilms' tumour from a WAGR patient.

A candidate gene (WT1) has recently been described for the 11p13 tumour-suppressor gene involved in the development of Wilms' tumour. This gene encodes a zinc finger protein which can bind to a specific DNA sequence. We have found a 226 base deletion in the mRNA from a unilateral Wilms' tumour, which would cause a frameshift that completely deletes the zinc finger domain. The tumour developed in a patient suffering from the WAGR syndrome, who had a constitutional 11p13 deletion, and so the 226 base deletion represents the inactivation of the remaining WT1 allele in the tumour. This provides further direct evidence that loss of function of WT1 is an essential step in the development of Wilms' tumour.

Thrombocytopenia-absent radius syndrome: a clinical genetic study.

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.

The association among negative symptoms, movement disorders, and frontal lobe psychological deficits in schizophrenic patients.

Neuropsychological tests of frontal lobe function were undertaken in 46 chronic schizophrenic patients who were also rated for movement disorders and negative symptoms. "High" and "low" SANS groups were formed by segregating around the median value. The "high" SANS group was found to differ significantly in terms of the severity of tardive dyskinesia (TD) and drug-induced parkinsonism, and frontal psychological tests. A possible mechanism is discussed within the context of known neostriatal psychological function.

Serum-dependent and cell cycle-dependent expression from a cytomegalovirus-based mammalian expression vector.

Cytomegalovirus-based mammalian expression vectors are widely used to drive the expression of transfected genes in cultured cells. Immunofluorescent staining of the WT1 protein in 3T3 and 293 cell clones, stably transfected with a cyomegalovirus (CMV) expression vector carrying a cDNA coding for the tumour suppressor protein WT1, showed extreme cell to cell variation in the amount of recombinant protein expressed, indicative of cell cycle dependence. This was investigated further by Western blot and FACS analysis which showed that WT1 protein expression was highest in S phase and almost absent in G0/G1. Northern blot analysis of cell clones expressing sense or antisense WT1 cDNAs regulated by the CMV promoter/enhancer showed that RNA expression was also cell cycle-dependent. Western blotting of cells expressing a luciferase reporter gene driven by the CMV promoter/enhancer also showed apparent cell cycle-dependent expression. We further demonstrated that the expression of these gene constructs was serum responsive with a 10-fold increase in expression occurring 2 h after the addition of serum. These results show that the CMV promoter/enhancer system varied in its response to serum and the cell cycle state. Therefore, care must be taken when interpreting any phenotypic alterations (or lack of them) produced in cells transfected with CMV-based expression vectors.

The influence of topography on the cognitive and psychopathological effects of tardive dyskinesia.

OBJECTIVE: The purpose of the study was to investigate the influence of the topography of dyskinetic movements on their effect on cognitive impairment and negative symptoms. METHOD: Eighty-four inpatients who satisfied DSM-III-R criteria for schizophrenia were rated for tardive dyskinesia, akathisia, and drug-induced parkinsonism, as well as negative symptoms, with the Scale for the Assessment of Negative Symptoms and for cognitive state with the Mini-Mental State examination. The subjects were then divided into those without tardive dyskinesia (N = 45), those with orofacial dyskinesia (N = 19), and those with limb-truncal dyskinesia (N = 20). Differences among the groups were assessed with multiple analysis of covariance (MANCOVA), with age, akathisia, and drug-induced parkinsonism ratings as the covariates. Post hoc Spjotvoll and Stoline tests were then undertaken. RESULTS: MANCOVA revealed a significant difference among the groups. Post hoc tests showed that the group with limb-truncal dyskinesia had significantly lower scores on the Mini-Mental State Examination and higher scores on the Scale for the Assessment of Negative Symptoms. The group with orofacial dyskinesia was significantly different from the nondyskinetic group only on the total score for the Scale for the Assessment of Negative Symptoms and the attention subscale. There were no significant differences between the dyskinetic groups. CONCLUSIONS: After correction for the important confounding variables of age, akathisia, and drug-induced parkinsonism scores, those with limb-truncal and, to a lesser degree, orofacial dyskinesia differed significantly from nondyskinetic comparison subjects in ratings of cognitive impairment and negative symptoms.

Autoregulation of the human WT1 gene promoter.

The human Wilms tumour suppressor gene, WT1, encodes a zinc-finger protein which can function as a transcriptional activator or suppressor. This study reports the analysis of the human WT1 gene promoter, and demonstrates that high levels of WT1 expression lead to autosuppression of the WT1 promoter. Deletion analyses of the promoter region implicate sequences 5' and 3' of the transcriptional start site as being crucial in WT1 autosuppression. Loss or alteration of this function of WT1 may be important in tumourigenesis.

Transactivation of the WT1 antisense promoter is unique to the WT1[+/-] isoform.

The Wilms' tumour suppressor gene, WT1, encodes a zinc finger transcription factor that has been shown to repress a variety of cellular promoters via binding to cognate DNA elements. Our earlier work identified an antisense WT1 promoter that contains WT1 consensus sites, but is transcriptionally activated by WT1. In this study, we demonstrate that, unlike previous reports of transcriptional regulation by WT1, transactivation of the antisense promoter is unique to a single isoform of WT1. Of the four alternatively spliced isoforms in which exon 5 (at splice I) or amino acid residues KTS (at splice II) are inserted or omitted, only the WT1 isoform containing splice I and omitting splice II (WT1[+/-]) displays transactivation. We demonstrate that transregulation variations observed with WT1 isoforms are not solely attributable to differential DNA binding by [+KTS] or [-KTS] isoforms. Thus, the transactivation of the antisense promoter displays an absolute requirement for exon 5, suggesting that interaction between WT1 and other cellular factors is necessary for this regulatory function.

Rapid and specific diagnosis of t(11;22) translocation in paediatric Ewing's sarcoma and primitive neuroectodermal tumours using RNA-PCR.

One case of paediatric Ewing's sarcoma and two peripheral primitive neuroectodermal tumours/extra-osseous Ewing's sarcoma were studied for the characteristic t(11;22) translocation, using a recently described RNA-polymerase chain reaction method (RNA-PCR). PCR products of the expected sizes were obtained from RNA derived from the Ewing's sarcoma and the peripheral primitive neuroectodermal tumours, but not from other paediatric malignancies. Direct sequencing of the RNA-PCR products confirmed the presence of the EWS-FLI-1 fusion transcript. In one case the presence of the translocation was confirmed by cytogenetic analysis. These results highlight the potential use of PCR for the rapid demonstration of diagnostically important tumour specific chromosome rearrangements.