Carrageenans with complex substitution patterns from red algae of the genus Erythroclonium

Extracellular polysaccharides from three Erythroclonium spp. were shown, by a combination of compositional, linkage analyses, and Fourier transform infrared and C-13-nuclear magnetic resonance spectroscopy, to be highly substituted carrageenans with at least five types of repeating disaccharide units. These are the carrabiose 2,4'-disulfate of iota-carrageenan, carrabiose 2-sulfate of alpha-carrageenan, the 6'-O-methylated counterparts of each of these repeating units, and 4',6'-O-(1-carboxyethylidene)carrabiose 2-sulfate. The polysaccharides also contain significant amounts of unsubstituted, 4-linked galactopyranose and small amounts of 4-linked 3-O-methylgalactopyranose and terminal glycosyl residues. The carrageenan preparations of the three species are similar, differing only in the proportions of some components. (C) 1998 Elsevier Science Ltd.

A novel tricopper(II) complex of a polyamine alcohol

The trinuclear copper(II) complex of a new polyamino alcohol ligand has been isolated; it exhibits a structure similar to that found at the active site of ascorbate oxidase.

Lemon oil to beta-cyclodextrin ratio effect on the inclusion efficiency of beta-cyclodextrin and the retention of oil volatiles in the complex

Microencapsulation of lemon oil was undertaken with beta-cyclodextrin using a precipitation method at the five lemon oil to beta-cyclodextrin ratios of 3:97, 6:94, 9:91, 12:88, and 15:85 (w/w) in order to determine the effect of the ratio of lemon oil to beta-cyclodextrin on the inclusion efficiency of beta-cyclodextrin for encapsulating oil volatiles. The retention of lemon oil volatiles reached a maximum at the lemon oil to beta-cyclodextrin ratio of 6:94; however, the maximum inclusion capacity of beta-cyclodextrin and a maximum powder recovery were achieved at the ratio of 12:88, in which the beta-cyclodextrin complex contained 9.68% (w/w) lemon oil. The profile and proportion of selected flavor compounds in the beta-cyclodextrin complex and the starting lemon oil were not significantly different.

Serious criminal offending and mental disorder - Case linkage study

Background A relationship exists between mental disorder and offending behaviours but the nature and extent of the association remains in doubt. Method Those convicted in the higher courts of Victoria between 1993 and 1995 had their pyschiatric history explored by case linkage to a register listing virtually all contacts with the public psychiatric services. Results Prior psychiatric contact was found in 25% or offenders, but the personality disorder and substance misuse accounted for much of this relationship. Schizophrenia and affective disorders were also over-represented, particularly those with coexisting substance misuse. Conclusions The increased offending in schizophrenia and affective illness is modest and may often be mediated by coexisting substance misuse. The risk of a serious crime being committed by someone with a major mental illness is small and does not justify subjecting them, as a group, to either increased institutional containment or greater coercion.

Targeting of a cholecystokinin-DNA complex to pancreatic cells in vitro and in vivo

The carboxy terminal octapeptide of cholecystokinin (CCK8) is a hormone that binds high affinity receptors in a number of tissues including pancreas and pancreatic tumours. As part of our studies to develop effective gene therapy for the treatment of pancreatic cancers, we have investigated various gene delivery systems that depend on CCK8 receptor targeting. In this paper,we describe the synthesis of a CCK8-DNA complex designed to deliver foreign DNA to cholecystokinin receptor-positive cells. CCK8 was ligated to avidin and then complexed to linearis biotinylated DNA (pSV-CAT). The uptake of P-32-labelled CCK8-DNA complex by rat pancreatic acini was linear with time over 4 h with 65-70% of uptake inhibited by 100 nM CCK8. The complex appeared to be internalised since it could not be removed by acid wash. When administered intra-arterially, the complex was rapidly removed from the circulation with no evidence of targeted delivery to the pancreas, However, following a single intraperitoneal dose, the pancreas accumulated-5- 8% of the total administered complex by 24 h. These results suggest that peptide-dependent gene delivery to CCK receptor positive cells in vivo is feasible but, when administered directly into the circulation, diffusional barriers across the endothelium may limit distribution to peripheral tissues. Intraperitoneal administration therefore may be a useful alternative for targeting the pancreas.

From sabotage to camouflage: viral evasion of cytotoxic T lymphocyte and natural killer cell-mediated immunity

The outcome of a virus infection is strongly influenced by interactions between host immune defences and virus 'anti-defence' mechanisms. For many viruses, their continued survival depends on, the speed of their attach: their capacity to replicate and transmit to uninfected hosts prior to their elimination by an effective immune response. In contrast, the success of persistent viruses lies in their capacity for immunological subterfuge: the evasion of host defence mechanisms by either mutation (covered elsewhere in this issue, by Gould and Bangham, pp. 321-328) or interference with the action of host cellular proteins that are important components of the immune response. This review will focus on the strategies employed by persistent viruses against two formidable host defences against virus infection: the CD8+ cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses.

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta 1 subunit gene SCN1B

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder(1). A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures(2). Segregation analysis suggests the majority of cases have complex inheritance(3) but rare families show apparent autosomal dominant: inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified(4,5). We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS(+)), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures(6). We now report linkage, in another large GEFS(+) family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta 1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Go-expression of the mutant pr subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Sequence heterogeneity in Parkinsonian speech

Parkinson's disease (PD) is a neurodegenerative movement disorder primarily due to basal ganglia dysfunction. While much research has been conducted on Parkinsonian deficits in the traditional arena of musculoskeletal limb movement, research in other functional motor tasks is lacking. The present study examined articulation in PD with increasingly complex sequences of articulatory movement. Of interest was whether dysfunction would affect articulation in the same manner as in limb-movement impairment. In particular, since very Similar (homogeneous) articulatory sequences (the tongue twister effect) are more difficult for healthy individuals to achieve than dissimilar (heterogeneous) gestures, while the reverse may apply for skeletal movements in PD, we asked which factor would dominate when PD patients articulated various grades of artificial tongue twisters: the influence of disease or a possible difference between the two motor systems. Execution was especially impaired when articulation involved a sequence of motor program heterogeneous in terms of place of articulation. The results are suggestive of a hypokinesic tendency in complex sequential articulatory movement as in limb movement. It appears that PD patients do show abnormalities in articulatory movement which are similar to those of the musculoskeletal system. The present study suggests that an underlying disease effect modulates movement impairment across different functional motor systems. (C) 1998 Academic Press.

The metal directed assembly of a trinuclear macrocyclic copper(II) complex

A trinuclear macrocyclic complex is reported from the metal directed condensation between melamine, formaldehyde and the Cu-II complex of a linear tetraamine.

Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice

Previously we described activating mutations of h beta(c), the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, h beta(c)FI Delta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the h beta(c)FI Delta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in h beta(c) may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic h beta(c) activation has the potential to contribute to pathological events in the central nervous system.

The first structurally characterized discrete dinuclear mu-cyano hexacyanoferrate complex

Mixed valence complexes containing ferro- and ferricyanide have been known for almost 300 years, but no dinuclear, non-polymeric examples of these complexes have been structurally characterized. Here we report the first such example, comprising ferrocyanide coordinated to a pentaaminecobalt(III) complex. This Fe-II-Co-III complex may be reversibly oxidized to the Fe-III-Co-III analogue.

Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease

High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15-17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a P-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine-aspartate interaction induces a 1.5 Angstrom N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba(67,95)]HIVPR and [Lys(7),Ile(33),Aba(67,95)]- HIVPR used in this work were shown to have very similar crystal structures.

Effect of disorder on quantum phase transitions in anisotropic XY spin chains in a transverse field

We present some exact results for the effect of disorder on the critical properties of an anisotropic XY spin chain in a transverse held. The continuum limit of the corresponding fermion model is taken and in various cases results in a Dirac equation with a random mass. Exact analytic techniques can then be used to evaluate the density of states and the localization length. In the presence of disorder the ferromagnetic-paramagnetic or Ising transition of the model is in the same universality class as the random transverse field Ising model solved by Fisher using a real-space renormalization-group decimation technique (RSRGDT). If there is only randomness in the anisotropy of the magnetic exchange then the anisotropy transition (from a ferromagnet in the x direction to a ferromagnet in the y direction) is also in this universality class. However, if there is randomness in the isotropic part of the exchange or in the transverse held then in a nonzero transverse field the anisotropy transition is destroyed by the disorder. We show that in the Griffiths' phase near the Ising transition that the ground-state energy has an essential singularity. The results obtained for the dynamical critical exponent, typical correlation length, and for the temperature dependence of the specific heat near the Ising transition agree with the results of the RSRODT and numerical work. [S0163-1829(99)07125-8].

Crystal and molecular structure of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and its iron(III) complex: an iron chelator with anti-tumour activity

Previous studies have demonstrated that 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and several other aroylhydrazone chelators possess anti-neoplastic activity due to their ability to bind intracellular iron. In this study we have examined the structure and properties of NIH and its Fe-III complex in order to obtain further insight into its anti-tumour activity. Two tridentate NIH ligands deprotonate upon coordination to Fe-III in a meridional fashion to form a distorted octahedral, high-spin complex. Solution electrochemistry of [Fe(NIH-H)(2)](+) shows that the trivalent oxidation state is dominant over a wide potential range and that the Fe-II analogue is not a stable form of this complex. The fact that [Fe(NIH-H)(2)](+) cannot-cycle between the Fe-II and Fe-III states suggests that the production of toxic free- radical species, e.g. OH. or O2(.-),is not part of this ligand's cytotoxic action. This suggestion is supported by cell culture experiments demonstrating that the addition of Fe-III to NIH prevents its anti-proliferative effect. The chemistry of this chelator and its Fe-III complex are discussed in the context of understanding its anti-tumour activity.

m144, a murine cytomegalovirus (MCMV)-encoded major histocompatibility complex class I homologue, confers tumor resistance to natural killer cell-mediated rejection

Until now, it has been unclear whether murine cytomegalovirus (MCMV)-encoded protein m144 directly regulates natural killer (NK) cell effector function and whether the effects of m144 are only strictly evident in the context of MCMV infection. We have generated clones of the transporter associated with antigen processing (TAP)-2-deficient RMA-S T lymphoma cell line and its parent cell line, RMA, that stably express significant and equivalent levels of m144. In vivo NK cell-mediated rejection of RMA-S-m144 lymphomas was reduced compared with rejection of parental or mock-transfected RMA-S clones, indicating the ability of m144 to regulate NK cell-mediated responses in vivo. Significantly, the accumulation of NK cells in the peritoneum was reduced in mice challenged with RMA-S-m144, as was the lytic activity of NK cells recovered from the peritoneum. Expression of m144 on RMA-S cells also conferred resistance to cytotoxicity mediated in vitro by interleukin 2-activated adherent spleen NK cells. In summary, the data demonstrate that m144 confers some protection from NK cell effector function mediated in the absence of target cell class I expression, but that in vivo the major effect of m144 is to regulate NK cell accumulation and activation at the site of immune challenge.