5-9岁儿童对常见病病因及其致病不确定性的认知发展

Research on children's naive concepts has previously tended to focus on the domains of physics and psychology, but more recently attention has turned to conceptual development in biology as a core domain of knowledge. Because of its familiarity, illness has been a popular topic for researchers in this domain. However, they have only studied the children’s understanding of its causes. Other aspects of illness, such as treatment and prognosis, have received little attention. This research addresses the development of 5- to 9-year-old children’s understanding of the causes of illness and their probabilities via open-ended and forced choice interviews. The results of this research are: 1) Most of the 5- to 7-year-old children used behavioral causes to explain illness, and the 9-year-old children primarily used biological causes to interpret illness. With age, more and more children selected psychological causes to explain illness. 2) Pre-school children did not over-generalize contagions to non-contagious illnesses. They used behavioral and biological causes to explain contagious illnesses. For non-contagious illnesses, they chose only behavioral causes. 3) Most of the children used only one kind of cause to explain illness. 4) Some preschool-aged children viewed outcomes of familiar causes of illness as probabilistic. With age, more and more could make uncertain predictions of illness. 5) The children’s understanding of the causes’ probabilities appeared to be based on naïve biology. 5- to 9-year-old children often made probabilistic predictions by analyzing a single cause of illness. 6) Children coming from higher educational backgrounds outperformed their counterparts coming from lower educational backgrounds with respect to understanding illness. 7) Specific knowledge acquired could generally improved the preschoolers’ understanding of causes of illness and their probabilities.

Butene catalytic cracking to propene and ethene over potassium modified ZSM-5 catalysts

Catalytic cracking of butene over potassium modified ZSM-5 catalysts was carried out in a fixed-bed microreactor. By increasing the K loading on the ZSM-5, butene conversion and ethene selectivity decreased almost linearly, while propene selectivity increased first, then passed through a maximum (about 50% selectivity) with the addition of ca. 0.7-1.0% K, and then decreased slowly with further increasing of the K loading. The reaction conditions were 620 degrees C, WHSV 3.5 h(-1), 0.1 MPa 1-butene partial pressure and 1 h of time on stream. Both by potassium modification of the ZSM-5 zeolite and by N(2) addition in the butene feed could enhance the selectivity towards propene effectively, but the catalyst stability did not show any improvement. On the other hand, addition of water to the butene feed could not only increase the butene conversion, but also improve the stability of the 0.7%K/ZSM-5 catalyst due to the effective removal of the coke formed, as demonstrated by the TPO spectra. XRD results indicated that the ZSM-5 structure of the 0.07% K/ZSM-5 catalyst was not destroyed even under this serious condition of adding water at 620 degrees C.

On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate

Ins(1,4,5,6)P4, a biologically active cell constituent, was recently advocated as a substrate of human Ins(3,4,5,6)P4 1-kinase (hITPK1), because stereochemical factors were believed relatively unimportant to specificity [Miller, G.J. Wilson, M.P. Majerus, P.W. and Hurley, J.H. (2005) Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-triphosphate 5/6-kinase. Mol. Cell. 18, 201-212]. Contrarily, we provide three examples of hITPK1 stereospecificity. hITPK1 phosphorylates only the 1-hydroxyl of both Ins(3,5,6)P3 and the meso-compound, Ins(4,5,6)P3. Moreover, hITPK1 has >13,000-fold preference for Ins(3,4,5,6)P4 over its enantiomer, Ins(1,4,5,6)P4. The biological significance of hITPK1 being stereospecific, and not physiologically phosphorylating Ins(1,4,5,6)P4, is reinforced by our demonstrating that Ins(1,4,5,6)P4 is phosphorylated (K(m) = 0.18 microM) by inositolphosphate-multikinase.

Towards the Industrial Production of Omega-3 Long Chain Polyunsaturated Fatty Acids from a Genetically Modified Diatom Phaeodactylum tricornutum.

The marine diatom Phaeodactylum tricornutum can accumulate up to 30% of the omega-3 long chain polyunsaturated fatty acid (LC-PUFA) eicosapentaenoic acid (EPA) and, as such, is considered a good source for the industrial production of EPA. However, P. tricornutum does not naturally accumulate significant levels of the more valuable omega-3 LC-PUFA docosahexaenoic acid (DHA). Previously, we have engineered P. tricornutum to accumulate elevated levels of DHA and docosapentaenoic acid (DPA) by overexpressing heterologous genes encoding enzyme activities of the LC-PUFA biosynthetic pathway. Here, the transgenic strain Pt_Elo5 has been investigated for the scalable production of EPA and DHA. Studies have been performed at the laboratory scale on the cultures growing in up to 1 L flasks a 3.5 L bubble column, a 550 L closed photobioreactor and a 1250 L raceway pond with artificial illumination. Detailed studies were carried out on the effect of different media, carbon sources and illumination on omega-3 LC-PUFAs production by transgenic strain Pt_Elo5 and wild type P. tricornutum grown in 3.5 L bubble columns. The highest content of DHA (7.5% of total fatty acids, TFA) in transgenic strain was achieved in cultures grown in seawater salts, Instant Ocean (IO), supplemented with F/2 nutrients (F2N) under continuous light. After identifying the optimal conditions for omega-3 LC-PUFA accumulation in the small-scale experiments we compared EPA and DHA levels of the transgenic strain grown in a larger fence-style tubular photobioreactor and a raceway pond. We observed a significant production of DHA over EPA, generating an EPA/DPA/DHA profile of 8.7%/4.5%/12.3% of TFA in cells grown in a photobioreactor, equivalent to 6.4 μg/mg dry weight DHA in a mid-exponentially growing algal culture. Omega-3 LC-PUFAs production in a raceway pond at ambient temperature but supplemented with artificial illumination (110 μmol photons m-2s-1) on a 16:8h light:dark cycle, in natural seawater and F/2 nutrients was 24.8% EPA and 10.3% DHA. Transgenic strain grown in RP produced the highest levels of EPA (12.8%) incorporated in neutral lipids. However, the highest partitioning of DHA in neutral lipids was observed in cultures grown in PBR (7.1%). Our results clearly demonstrate the potential for the development of the transgenic Pt_Elo5 as a platform for the commercial production of EPA and DHA.

Effects of the novel (Pro(3))GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

AIMS/HYPOTHESIS: This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide.

METHODS: Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice.

RESULTS: In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small.

CONCLUSIONS/INTERPRETATION: These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

Tyrosine phosphorylated SOCS-3 inhibits STAT activation but binds p120-RasGAP and activates Ras

Suppressors of cytokine signalling (SOCS, also known as CIS and SSI) are encoded by immediate early genes that act in a feedback loop to inhibit cytokine responses and activation of 'signal transducer and activator of transcription' (STAT). Here we show that SOCS-3 is strongly tyrosine-phosphorylated in response to many growth factors, including interleukin-2 (IL-2), erythropoietin (EPO), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The principal phosphorylation sites on SOCS-3 are residues 204 and 221 at the carboxy terminus, and upon phosphorylation tyrosine 221 interacts with the Ras inhibitor p120 RasGAP. After IL-2 stimulation, phosphorylated SOCS-3 strongly inhibits STAT5 activation but, by binding to RasGAP, maintains activation of extracellular-signal-regulated kinase (ERK). A tyrosine mutant of SOCS-3 still blocks STAT phosphorylation, but also strongly inhibits IL-2-dependent activation of ERK and cell proliferation. Moreover, it also inhibits EPO- and PDGF-induced proliferation and ERK activation. Therefore, although SOCS proteins inhibit growth-factor responses, tyrosine phosphorylation of SOCS-3 can ensure cell survival and proliferation through the Ras pathway.

Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate.

Full-length transient receptor potential (TRP) cation channel TRPC4alpha and shorter TRPC4beta lacking 84 amino acids in the cytosolic C terminus are expressed in smooth muscle and endothelial cells where they regulate membrane potential and Ca(2+) influx. In common with other "classical" TRPCs, TRPC4 is activated by G(q)/phospholipase C-coupled receptors, but the underlying mechanism remains elusive. Little is also known about any isoform-specific channel regulation. Here we show that TRPC4alpha but not TRPC4beta was strongly inhibited by intracellularly applied phosphatidylinositol 4,5-bisphosphate (PIP(2)). In contrast, several other phosphoinositides (PI), including PI(3,4)P(2), PI(3,5)P(2), and PI(3,4,5)P(3), had no effect or even potentiated TRPC4alpha indicating that PIP(2) inhibits TRPC4alpha in a highly selective manner. We show that PIP(2) binds to the C terminus of TRPC4alpha but not that of TRPC4beta in vitro. Its inhibitory action was dependent on the association of TRPC4alpha with actin cytoskeleton as it was prevented by cytochalasin D treatment or by the deletion of the C-terminal PDZ-binding motif (Thr-Thr-Arg-Leu) that links TRPC4 to F-actin through the sodium-hydrogen exchanger regulatory factor and ezrin. PIP(2) breakdown appears to be a required step in TRPC4alpha channel activation as PIP(2) depletion alone was insufficient for channel opening, which additionally required Ca(2+) and pertussis toxin-sensitive G(i/o) proteins. Thus, TRPC4 channels integrate a variety of G-protein-dependent stimuli, including a PIP(2)/cytoskeleton dependence reminiscent of the TRPC4-like muscarinic agonist-activated cation channels in ileal myocytes.

Sequential C-H and C-Ru bond formation and cleavage during the thermally induced rearrangement of aryl ruthenium(II) complexes with [C6H3(CH2NMe2)(2)-2,6](-) as a bidentate eta(2)-C,N coordinated ligand. The crystal structures of the isomeric pairs [RuCl{eta(6)-C10H14}{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n}] (n = 4 or 6) and [Ru(eta(5)-C5H5){(eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n} (PPH3)] (n = 4 or 6)

New air-stable ruthenium(II) complexes that contain the aryldiamine ligand [C6H3(CH2-NMe2)(2)-2,6](-) (NCN) are described. These complexes are [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(6)-C10H14)] (2; C10H14 = p-cymene = C6H4Me-Pr-i-4), [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(5)-C5H5)(PPh3)] (5), and their isomeric forms [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(6)-C10H14)] (3) and [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(5)-C5H5)(PPh3)] (6), respectively. Complex 2 has been prepared from the reaction of [Li(NCN)](2) with [RuCl2(eta(6)-C10H14)](2), whereas complex 5 has been prepared by the treatment of [RuCl{eta(3)-N,C,N-C6H3(CH2NMe2)(2)-2,6}(PPh3)] (4) with [Na(C5H5)](n). Both 2 and 5 are formally 18-electron ruthenium(II) complexes in which the monoanionic potentially tridentate coordinating ligand NCN is eta(2)-C,N-bonded, In solution (halocarbon solvent at room temperature or in aromatic solvents at elevated temperature), the intramolecular rearrangements of 2 and 5 afford complexes 3 and 6, respectively. This is a result of a shift of the metal-C-aryl bond from position-1 to position-3 on the aromatic ring of the NCN ligand. The mechanism of the isomerization is proposed to involve a sequence of intramolecular oxidative addition and reductive elimination reactions of both aromatic and aliphatic C-H bonds. This is based on results from deuterium labeling, spectroscopic studies, and some kinetic experiments. The mechanism is proposed to contain fully reversible steps in the case of 5, but a nonreversible step involving oxidative addition of a methyl NCH2-H bond in the case of 2. The solid-state structures of complexes 2, 3, 5, and 6 have been determined by single-crystal X-ray diffraction. A new dinuclear 1,4-phenylene-bridged bisruthenium(II) complex, [1,4-{RuCl(eta(6)-C10H14)}(2){C-6(CH2NMe2)(4)-2,3,5,6-C,N,C',N'}] (9) has also been prepared from the dianionic ligand [C-6(CH2NMe2)(4)-2,3,5,6](2-) (C2N4). The C2N4 ligand is in an eta(2)-C,N-eta(2)-C',N'-bis(bidentate) bonding mode. Compound 9 does not isomerize in solution (halocarbon solvent), presumably because of the absence of an accessible C-aryl-H bond. Complex 9 could not be isolated in an analytically pure form, probably because of its high sensitivity to air and very low solubility, which precludes recrystallization.

Versatile N,C,N coordination behavior of a monoanionic aryldiamine ligand in ruthenium(II) complexes: Syntheses and crystal structures of [Ru-II(C6H3(CH(2)NMe(2))(2)-2,6)X(L)] (L equals norbornadiene, X=Cl, SO3CF3; L=PPh(3), X=I) and [Ru-II{C6H3(CH(2)NMe(2))(2)-2,6}(2,2':6:2''-terpyridine)]Cl

The monoanionic ligand [C6H3(CH(2)NMe(2))(2)-2,6](-), a potentially terdentate N,C,N bonding system, has been employed to synthesize a series of new ruthenium(II) complexes [Ru{C6H3(CH(2)NMe(2))(2)-2,6}X(L)] (L = PPh(3) X = Cl (2a), I (2b); L = norbornadiene (nbd), X = Cl (4), eta(1)-OSO2CF3 (5)) and [Ru{C6H3(CH(2)NMe(2))(2)-2,6}(2,2':6',2 ''-terpyridine)]Cl (3). X-ray crystal structures of 2b and 3-5 have been determined, in which the N,C,N coordination geometry with respect to the metal center is found to differ considerably. In each complex the aryldiamine ligand is terdentate, eta(3)-N,C,N-bonded as a six electron donor system. However, depending on the other ligands in the Ru(II) coordination sphere, this ligand demonstrates considerable flexibility in adopting coordination geometries which range from meridional in 3 through pseudomeridional in 2b to pseudofacial in 4 and 5. In the structures of 4 and 5 significant distortions of the aryl ring, involving bending of the six-membered ring into a boatlike conformation, are found. The different combinations of the N,C,N ligand with sets of other ligands lead to a range of metal geometries, i.e. square pyramidal in 2b, octahedral in 3, and bicapped tetrahedral in 4 and 5.

Role of basal extracellular Ca2+ entry during 5-HT-induced vasoconstriction of canine pulmonary arteries.

1. Measurements of artery contraction, cytosolic [Ca(2+)], and Ca(2+) permeability were made to examine contractile and cytosolic [Ca(2+)] responses of canine pulmonary arteries and isolated cells to 5-hydroxytryptamine (5-HT), and to determine the roles of intracellular Ca(2+) release and extracellular Ca(2+) entry in 5-HT responses. 2. The EC(50) for 5-HT-mediated contractions and cytosolic [Ca(2+)] increases was approximately 10(-7) M and responses were inhibited by ketanserin, a 5-HT(2A)-receptor antagonist. 3. 5-HT induced cytosolic [Ca(2+)] increases were blocked by 20 microM Xestospongin-C and by 2-APB (IC(50)=32 microM inhibitors of InsP(3) receptor activation. 4. 5-HT-mediated contractions were reliant on release of InsP(3) but not ryanodine-sensitive Ca(2+) stores. 5. 5-HT-mediated contractions and cytosolic [Ca(2+)] increases were partially inhibited by 10 microM nisoldipine, a voltage-dependent Ca(2+) channel blocker. 6. Extracellular Ca(2+) removal reduced 5-HT-mediated contractions further than nisoldipine and ablated cytosolic [Ca(2+)] increases and [Ca(2+)] oscillations. Similar to Ca(2+) removal, Ni(2+) reduced cytosolic [Ca(2+)] and [Ca(2+)] oscillations. 7. Mn(2+) quench of fura-2 and voltage-clamp experiments showed that 5-HT failed to activate any significant voltage-independent Ca(2+) entry pathways, including store-operated and receptor-activated nonselective cation channels. Ni(2+) but not nisoldipine or Gd(3+) blocked basal Mn(2+) entry. 8. Voltage-clamp experiments showed that simultaneous depletion of both InsP(3) and ryanodine-sensitive intracellular Ca(2+) stores activates a current with linear voltage dependence and a reversal potential consistent with it being a nonselective cation channel. 5-HT did not activate this current. 9. Basal Ca(2+) entry, rather than CCE, is important to maintain 5-HT-induced cytosolic [Ca(2+)] responses and contraction in canine pulmonary artery.

Pressure effect on vibrational frequency and dephasing of 1-alkyl-3-methylimidazolium hexafluorophosphate ionic liquids

Raman spectra in the range of the totally symmetric stretching mode of the [PF6]− anion, νs(PF6), have been measured for 1-alkyl-3-methylimidazolium ionic liquids [CnC1im][PF6], for n = 4, 6, and 8, as a function of pressure at room temperature. The ionic liquids [C6C1im][PF6] and [C8C1im][PF6] remain in an amorphous phase up to 3.5 GPa, in contrast to [C4C1im][PF6], whichcrystallizes above ∼0.5 GPa. Equations of state based either on a group contribution model or Carnahan-Starling-van der Waals model have been used to estimate the densities of the ionic liquids at high pressures. The shifts of the vibrational frequency of νs(PF6) with density observed in [C6C1im][PF6] and in [C8C1im][PF6] have been calculated by a hard-sphere model of a pseudo-diatomic solute under short-range repulsive interactions with the neighboring particles. The stochastic model of Kubo for vibrational dephasing has been used to obtain the amplitude of vibrational frequency fluctuation, ⟨Δω 2⟩, and the relaxation time of frequency fluctuation, τ c , as a function of density by Raman band shape analysis of the νs(PF6) mode of [C6C1im][PF6] and [C8C1im][PF6].

Helping the most vulnerable out of the poverty trap and reducing inequality: Policies, strategies, and services for individuals with Autism Spectrum Disorder, including intellectual and neurodevelopmental disabilities: Benchmarking Autism Services Efficacy: BASE Project (Volume 3) Secondary Data analysis

1) Executive Summary
Legislation (Autism Act NI, 2011), a cross-departmental strategy (Autism Strategy 2013-2020) and a first action plan (2013-2016) have been developed in Northern Ireland in order to support individuals and families affected by Autism Spectrum Disorder (ASD) without a prior thorough baseline assessment of need. At the same time, there are large existing data sets about the population in NI that had never been subjected to a secondary data analysis with regards to data on ASD. This report covers the first comprehensive secondary data analysis and thereby aims to inform future policy and practice.
Following a search of all existing, large-scale, regional or national data sets that were relevant to the lives of individuals and families affected by Autism Spectrum Disorder (ASD) in Northern Ireland, extensive secondary data analyses were carried out. The focus of these secondary data analyses was to distill any ASD related data from larger generic data sets. The findings are reported for each data set and follow a lifespan perspective, i.e., data related to children is reported first before data related to adults.
Key findings:
Autism Prevalence:
Of children born in 2000 in the UK,
• 0.9% (1:109) were reported to have ASD, when they were 5-year old in 2005;
• 1.8% (1:55) were reported to have ASD, when they were 7-years old in 2007;
• 3.5% (1:29) were reported to have ASD, when they were 11-year old in 2011.
In mainstream schools in Northern Ireland
• 1.2% of the children were reported to have ASD in 2006/07;
• 1.8% of the children were reported to have ASD in 2012/13.

Economic Deprivation:
• Families of children with autism (CWA) were 9%-18% worse off per week than families of children not on the autism spectrum (COA).
• Between 2006-2013 deprivation of CWA compared to COA nearly doubled as measured by eligibility for free school meals (from near 20 % to 37%)
• In 2006, CWA and COA experienced similar levels of deprivation (approx. 20%), by 2013, a considerable deprivation gap had developed, with CWA experienced 6% more deprivation than COA.
• Nearly 1/3 of primary school CWA lived in the most deprived areas in Northern Ireland.
• Nearly ½ of children with Asperger’s Syndrome who attended special school lived in the most deprived areas.

Unemployment:
• Mothers of CWA were 6% less likely to be employed than mothers of COA.
• Mothers of CWA earned 35%-56% less than mothers of COA.
• CWA were 9% less likely to live in two income families than COA.

Health:
• Pre-diagnosis, CWA were more likely than COA to have physical health problems, including walking on level ground, speech and language, hearing, eyesight, and asthma.
• Aged 3 years of age CWA experienced poorer emotional and social health than COA, this difference increased significantly by the time they were 7 years of age.
• Mothers of young CWA had lower levels of life satisfaction and poorer mental health than mothers of young COA.
Education:
• In mainstream education, children with ASD aged 11-16 years reported less satisfaction with their social relationships than COA.
• Younger children with ASD (aged 5 and 7 years) were less likely to enjoy school, were bullied more, and were more reluctant to attend school than COA.
• CWA attended school 2-3 weeks less than COA .
• Children with Asperger’s Syndrome in special schools missed the equivalent of 8-13 school days more than children with Asperger’s Syndrome in mainstream schools.
• Children with ASD attending mainstream schooling were less likely to gain 5+ GCSEs A*-C or subsequently attend university.



Further and Higher Education:
• Enrolment rates for students with ASD have risen in Further Education (FE), from 0% to 0.7%.
• Enrolment rates for students with ASD have risen in Higher Education (HE), from 0.28% to 0.45%.
• Students with ASD chose to study different subjects than students without ASD, although other factors, e.g., gender, age etc. may have played a part in subject selection.
• Students with ASD from NI were more likely than students without ASD to choose Northern Irish HE Institutions rather than study outside NI.

Participation in adult life and employment:
• A small number of adults with ASD (n=99) have benefitted from DES employment provision over the past 12 years.
• It is unknown how many adults with ASD have received employment support elsewhere (e.g. Steps to Work).
•
Awareness and Attitudes in the General Population:
• In both the 2003 and 2012 NI Life and Times Survey (NILTS), NI public reported positive attitudes towards the inclusion of children with ASD in mainstream education (see also BASE Project Vol. 2).

Gap Analysis Recommendations:
This was the first comprehensive secondary analysis with regards to ASD of existing large-scale data sets in Northern Ireland. Data gaps were identified and further replications would benefit from the following data inclusion:
• ASD should be recorded routinely in the following datasets:
o Census;
o Northern Ireland Survey of Activity Limitation (NISALD);
o Training for Success/Steps to work; Steps to Success;
o Travel survey;
o Hate crime; and
o Labour Force Survey.
• Data should be collected on the destinations/qualifications of special school leavers.
• NILT Survey autism module should be repeated in 5 years time (2017) (see full report of 1st NILT Survey autism module 2012 in BASE Project Report Volume 2).
• General public attitudes and awareness should be assessed for children and young people, using the Young Life and Times Survey (YLT) and the Kids Life and Times Survey (KLT); (this work is underway, Dillenburger, McKerr, Schubolz, & Lloyd, 2014-2015).
 

Targeting of photooxidative damage on single-stranded DNA representing the bcr-abl chimeric gene using oligonucleotide-conjugates containing [Ru(phen)3](2+)-like photosensitiser groups

Photooxidative damage was induced predominantly at a single guanine base in a target DNA by irradiation (lambda > 330 nm) in the presence of complementary oligodeoxynucleotide conjugates (ODN-5'-linker-[Ru(phen)3]2+) (phen = 1,10-phenanthroline). The target DNA represents the b2a2 variant of the chimeric bcr-abl gene implicated in the pathogenesis of chronic myeloid leukaemia, and the sequence of the 17mer ODN component of the conjugate (3' G G T A G T T A T T C C T T C T T 5') was complementary to the junction region of the sense strand sequence of this oncogene. Two different conjugates were prepared, both of them by reaction of the appropriate succinimide ester with 5'-hexylamino-derivatised 17mer ODN. In Ru-ODN-1 (7) the linker was -(CH2)6-NHCO-bpyMe (-bpyMe = 4'-[4-methyl-2,2'-bipyridyl]), whereas in Ru-ODN-2 (13) it was -(CH2)6-NHCO-(CH2)3-CONH-phen. Photoexcitation of either of the conjugates when hybridised with the 32P-5'-end-labelled target 34mer 5'T G A C C A T C A A T A A G G A A G A A G21 C C C T T C A G C G G C C 3' (ODN binding site underlined) led to an alkali-labile site predominantly (> 90%) at the G21 base, which is at the junction of double-stranded and single-stranded regions of the hybrid. Greater yields were found with Ru-ODN-1 (7) than with Ru ODN-2 (13). In contrast to this specific cleavage with Ru-ODN-1 (7) or Ru-ODN-2 (13), alkali-labile sites were generated at all guanines when the 34mer was photolysed in the presence of the free sensitiser [Ru(phen)3]2+. Since [Ru(phen)3]2+ was shown to react with 2'-deoxyguanosine to form the diastereomers of a spiroiminodihydantoin derivative (the product from 1O2 reaction), 1O2 might also be an oxidizing species in the case of Ru-ODN-1 (7) and Ru-ODN-2 (13). Therefore to determine the range of reaction, a series of 'variant' targets was prepared, in which G21 was replaced with a cytosine and a guanine substituted for a base further towards the 3'-end (e.g. Variant 3; 5'T G A C C A T C A A T A A G G A A G A A C C G23 C T T C A G C G G32 C C3'). While it was noted that efficient reaction took place at distances apparently remote from the photosensitiser (e.g at G32, but not G23 for Variant 3), this effect could be attributed to hairpinning of the single-stranded region of the target. These results are therefore consistent with the photooxidative damage being induced by a reaction close to the photosensitiser rather than by a diffusible species such as 1O2.

5.9-keV Mn K-shell X-ray luminosity from the decay of 55Fe in Type Ia supernova models

We show that the X-ray line flux of the Mn Kα line at 5.9 keV from the decay of 55Fe is a promising diagnostic to distinguish between Type Ia supernova (SN Ia) explosion models. Using radiation transport calculations, we compute the line flux for two three-dimensional explosion models: a near-Chandrasekhar mass delayed detonation and a violent merger of two (1.1 and 0.9 M⊙) white dwarfs. Both models are based on solar metallicity zero-age main-sequence progenitors. Due to explosive nuclear burning at higher density, the delayed-detonation model synthesizes ˜3.5 times more radioactive 55Fe than the merger model. As a result, we find that the peak Mn Kα line flux of the delayed-detonation model exceeds that of the merger model by a factor of ˜4.5. Since in both models the 5.9-keV X-ray flux peaks five to six years after the explosion, a single measurement of the X-ray line emission at this time can place a constraint on the explosion physics that is complementary to those derived from earlier phase optical spectra or light curves. We perform detector simulations of current and future X-ray telescopes to investigate the possibilities of detecting the X-ray line at 5.9 keV. Of the currently existing telescopes, XMM-Newton/pn is the best instrument for close (≲1-2 Mpc), non-background limited SNe Ia because of its large effective area. Due to its low instrumental background, Chandra/ACIS is currently the best choice for SNe Ia at distances above ˜2 Mpc. For the delayed-detonation scenario, a line detection is feasible with Chandra up to ˜3 Mpc for an exposure time of 106 s. We find that it should be possible with currently existing X-ray instruments (with exposure times ≲5 × 105 s) to detect both of our models at sufficiently high S/N to distinguish between them for hypothetical events within the Local Group. The prospects for detection will be better with future missions. For example, the proposed Athena/X-IFU instrument could detect our delayed-detonation model out to a distance of ˜5 Mpc. This would make it possible to study future events occurring during its operational life at distances comparable to those of the recent supernovae SN 2011fe (˜6.4 Mpc) and SN 2014J (˜3.5 Mpc).

Síntese e transformações de compostos do tipo pirazol e 1,2,3-triazol

Compostos do tipo pirazol e 1,2,3-triazol encontram-se presentes em inúmeras moléculas biologicamente ativas. Muitos fármacos atualmente comercializados ou em fase de estudos clínicos contêm na sua estrutura base núcleos de pirazol ou 1,2,3-triazol. Por isso, estes compostos têm sido alvo de intensa pesquisa na procura de novas moléculas com potenciais aplicações medicinais e agroquímicas. Nesta dissertação são descritas novas vias de síntese de novos compostos do tipo pirazol e 1,2,3-triazol. No primeiro capítulo apresenta-se uma breve revisão bibliográfica sobre a atividade biológica, ocorrência natural e métodos de síntese de pirazóis e seus derivados. O segundo capítulo foca-se na síntese de (E)-2-estiril-3-halo-4H-cromen-4-onas e sua transformação em 3(5)-aril-5(3)-[2-(2-hidroxifenil)-2-oxoetil-1H-pirazóis. Em primeiro lugar faz-se uma revisão bibliográfica sobre as (E)-2-estiril-4H-cromen-4-onas e a sua semelhança estrutural com as flavonas, a sua importância e ocorrência natural e métodos de síntese. São ainda abordadas as metodologias mais utilizadas para a síntese de derivados halogenados de (E)-2-estiril-4H-cromen-4-onas. Seguidamente são apresentados e discutidos os resultados da síntese de (E)-3-bromo-2-estiril-4H-cromen-4-onas através da reação de 5-aril-3-hidroxi-1-(2-hidroxifenil)penta-2,4-dien-1-onas com NBS, sob irradiação com micro-ondas, tendo sido estabelecida uma nova metodologia mais eficiente, rápida e regiosseletiva para a síntese de (E)-3-bromo-2-estiril-4H-cromen-4-onas, na ausência de solvente. São igualmente apresentados os resultados da síntese regiosseletiva de (E)-2-estiril-3-iodo-4H-cromen-4-onas através da reação de 5-aril-3-hidroxi-1-(2-hidroxifenil)penta-2,4-dien-1-onas com NIS e TFA/TFAA/NaOAc. Em ambos os métodos de halogenação desenvolvidos, obtiveram-se como produtos secundários as (E)-2-estiril-4H-cromen-4-onas correspondentes. Seguidamente é apresentado o estudo da reação de (E)-2-estiril-3-halo-4H-cromen-4-onas com hidrato de hidrazina. Ao contrário do esperado, obtiveram-se os 3(5)-aril-5(3)-[2-(2-hidroxifenil)-2-oxoetil-1H-pirazóis através de uma reação de adição conjugada 1,6-, de hidrazina à posição C- da cromona com consequente abertura do anel, seguida de uma adição conjugada 1,4- intramolecular. Estes resultados demonstraram que esta reação segue um mecanismo diferente daquele que está reportado na literatura para a reação de (E)-2-estiril-4H-cromen-4-onas não halogenadas em C-3 com hidrato de hidrazina. No terceiro capítulo apresenta-se uma breve revisão bibliográfica sobre as propriedades, aplicações e metodologias de síntese de 1,2,3-triazóis, dando mais relevância às reações de cicloadição 1,3-dipolar e de “click-chemistry”. Seguidamente descrevem-se os resultados obtidos na reação de (E)-5(3)-estiril-3(5)-(2-hidroxifenil)-1H-pirazóis com a azida de sódio para obtenção de díades pirazol-1,2,3-triazol. No entanto esta reação deu origem a novos 5(3)-(2-aril-2-azidoetil)-3(5)-(2-hidroxifenil)-1H-pirazóis e não às díades pirazol-1,2,3-triazol pretendidas. Como o resultado não foi o esperado, desenvolveu-se outra metodologia de síntese, que envolve, num primeiro, a reação de (E)-2-estiril-4H-cromen-4-onas com azida de sódio, dando origem a 5(4)-aril-4(5)-(cromon-2-il)-1H-1,2,3-triazóis. No passo seguinte, efetuou-se a reação destes compostos com hidrato de hidrazina tendo ocorrido a formação das diades 5(4)-aril-4(5)-[3(5)-(2-hidroxifenil)-1H-pirazol-5(3)-il]-1H-1,2,3-triazol pretendidas. No quarto capítulo, estudou-se a reatividade de (E)-5(3)-estiril-3(5)-(2-hidroxifenil)-1H-pirazóis em reações de iodação com vista à obtenção de 4-iodo-1H-pirazóis. Apresenta-se uma breve revisão bibliográfica sobre os diferentes métodos descritos na literatura para a iodação de compostos heterocíclicos aromáticos, nomeadamente para a obtenção de 4-iodo-1H-pirazóis. Dos vários sistemas de iodação testados, o sistema oxidativo I2/CAN foi o que deu melhores resultados na iodação dos (E)-5(3)-estiril-3(5)-(2-hidroxifenil)-1H-pirazóis. Este método permitiu iodar a posição C-4 do núcleo de pirazol apenas para os derivados que possuem o grupo nitro ou o átomo de cloro no anel do grupo estirilo, obtendo-se o 3(5)-(2-hidroxifenil)-4-iodo-5(3)-(4-nitrofenil)vinil-1H-pirazol e o 5(3)-(4-clorofenil)vinil)-3(5)-(2-hidroxi-5-iodofenil)-4-iodo-1H-pirazol; no entanto, para os restantes derivados, verificou-se apenas a iodação nas posições ativadas do anel fenólico. Todos os novos compostos sintetizados foram caraterizados estruturalmente recorrendo a estudos de espetroscopia de ressonância magnética nuclear (RMN) mono e bidimensionais. Sempre que possível, para uma caraterização estrutural mais completa, foram efetuados espetros de massa (EM) e análises elementares ou espetros de massa de alta resolução (EMAR) para todos os novos compostos sintetizados. Finalmente são apresentadas as conclusões gerais deste trabalho e perspetivas futuras.