Synthesis, spectral and electrochemical properties of donor/acceptor substituted fluoroarylporphyrins

Spectroscopic and electrochemical redox properties of a series of fluorinated porphyrins bearing donor-acceptor groups and their Zn(II) and Cu(II) derivatives are presented. The magnitude of the ring reduction potentials and charge transfer properties derived from spectral data depend on the nature and position of the substituent(s), (nitro/dimethylamino) and the central metal ions.

Donor strategy under the fungibility of foreign aid

We develop a political–economic model of aid fungibility: a part of aid is diverted away from its intended target by lobby groups. The size of this diversion – the degree of aid fungibility – is determined endogenously by the recipient government. The donor can affect the equilibrium degree of fungibility by choosing both the size of aid and the timing of its decision. We derive a condition under which the donor's reaction to fungibility is to reduce the amount of aid. Under this condition, if the donor acts as a follower, both the donor and the target group are better off.

Tied aid, unemployment and welfare

The effect of foreign aid on the welfare levels of both the recipient and the donor country has been a much analysed topic for research in both the theory of international trade and development economics. In the development economics literature, concerns have been raised since the 1960s on the possible adverse effect of foreign aid on domestic savings and growth.1 The trade theory literature in this respect is much older and dates back to the 1920s when Professors Keynes and Ohlin debated on the effect of foreign aid on international terms of trade.2 Ever since, the terms of trade effect has been the cornerstone in the analysis of the welfare effect of foreign aid in the trade theory literature.3 After some early confusion, it is now well established that in a Walrasian stable world economy with two countries, a necessary condition for foreign aid to have perverse effects is that there is some distortion in either of the two countries.4 It is also known that, under normality and substitutability of goods, untied aid cannot be strictly Pareto-improving in a tariff distorted world.5

Human parvovirus B19: tissue persistence and prevalence of prototypic and new variants

Human parvovirus B19 is a minute ssDNA virus causing a wide variety of diseases, including erythema infectiosum, arthropathy, anemias, and fetal death. After primary infection, genomic DNA of B19 has been shown to persist in solid tissues of not only symptomatic but also of constitutionally healthy, immunocompetent individuals. In this thesis, the viral DNA was shown to persist as an apparently intact molecule of full length, and without persistence-specific mutations. Thus, although the mere presence of B19 DNA in tissue can not be used as a diagnostic criterion, a possible role in the pathogenesis of diseases e.g. through mRNA or protein production can not be excluded. The molecular mechanism, the host-cell type and the possible clinical significance of B19 DNA tissue persistence are yet to be elucidated. In the beginning of this work, the B19 genomic sequence was considered highly conserved. However, new variants were found: V9 was detected in 1998 in France, in serum of a child with aplastic crisis. This variant differed from the prototypic B19 sequences by ~10 %. In 2002 we found, persisting in skin of constitutionally healthy humans, DNA of another novel B19 variant, LaLi. Genetically this variant differed from both the prototypic sequences and the variant V9 also by ~10%. Simultaneously, B19 isolates with DNA sequences similar to LaLi were introduced by two other groups, in the USA and France. Based on phylogeny, a classification scheme based on three genotypes (B19 types 1-3) was proposed. Although the B19 virus is mainly transmitted via the respiratory route, blood and plasma-derived products contaminated with high levels of B19 DNA have also been shown to be infectious. The European Pharmacopoeia stipulates that, in Europe, from the beginning of 2004, plasma pools for manufacture must contain less than 104 IU/ml of B19 DNA. Quantitative PCR screening is therefore a prerequisite for restriction of the B19 DNA load and obtaining of safe plasma products. Due to the DNA sequence variation among the three B19 genotypes, however, B19 PCR methods might fail to detect the new variants. We therefore examined the suitability of the two commercially available quantitative B19 PCR tests, LightCycler-Parvovirus B19 quantification kit (Roche Diagnostics) and RealArt Parvo B19 LC PCR (Artus), for detection, quantification and differentiation of the three B19 types known, including B19 types 2 and 3. The former method was highly sensitive for detection of the B19 prototype but was not suitable for detection of types 2 and 3. The latter method detected and differentiated all three B19 virus types. However, one of the two type-3 strains was detected at a lower sensitivity. Then, we assessed the prevalence of the three B19 virus types among Finnish blood donors, by screening pooled plasma samples derived from >140 000 blood-donor units: none of the pools contained detectable levels of B19 virus types 2 or 3. According to the results of other groups, B19 type 2 was absent also among Danish blood-donors, and extremely rare among symptomatic European patients. B19 type 3 has been encountered endemically in Ghana and (apparently) in Brazil, and sporadical cases have been detected in France and the UK. We next examined the biological characteristics of these virus types. The p6 promoter regions of virus types 1-3 were cloned in front of a reporter gene, the constructs were transfected into different cell lines, and the promoter activities were measured. As a result, we found that the activities of the three p6 promoters, although differing in sequence by >20%, were of equal strength, and most active in B19-permissive cells. Furthermore, the infectivity of the three B19 types was examined in two B19-permissive cell lines. RT-PCR revealed synthesis of spliced B19 mRNAs, and immunofluorescence verified the production of NS1 and VP proteins in the infected cells. These experiments suggested similar host-cell tropism and showed that the three virus types are strains of the same species, i.e. human parvovirus B19. Last but not least, the sera from subjects infected in the past either with B19 type 1 or type 2 (as evidenced by tissue persistence of the respective DNAs), revealed in VP1/2- and VP2-EIAs a 100 % cross-reactivity between virus types 1 and 2. These results, together with similar studies by others, indicate that the three B19 genotypes constitute a single serotype.

Negative experiences and donor return: An examination of the role of asking for something different

BACKGROUND Negative donation experiences, including vasovagal reactions, deter donor retention. However, whether this deterrence effect varies as a function of whole blood (WB) donation history and requests to donate the same or a different product remains unclear. STUDY DESIGN AND METHODS The responses of 894 eligible WB donors who had been approached to convert to plasmapheresis and 954 eligible first-time plasmapheresis donors who had been surveyed on their last donation experience and their intention to donate plasma were considered. This information was matched with individual vasovagal reaction records, deferral category, WB donation history, and subsequent donation behavioral data obtained from the blood collection agency. RESULTS Path analysis indicated that the application of a deferral and an officially recorded vasovagal reaction decreased donors' intentions to continue plasmapheresis donation, but had no effect on WB donors' intentions to convert to plasmapheresis. Consistent with past findings, vasovagal reactions occurred more frequently with female and inexperienced donors. CONCLUSION Experiencing vasovagal reactions and deferrals may not universally deter donors from continuing to donate. Rather, the offer to convert to another form of donation—in this instance, plasmapheresis—after experiencing a negative donation event while donating WB may be sufficient to eliminate the deterrence effect on retention.

Characterization of genomic diversity in extraintestinal pathogenic Escherichia coli (ExPEC) and development of a diagnostic DNA microarray for the differentiation of ExPEC isolates causing urinary tract infections

Extraintestinal pathogenic Escherichia coli (ExPEC) represent a diverse group of strains of E. coli, which infect extraintestinal sites, such as the urinary tract, the bloodstream, the meninges, the peritoneal cavity, and the lungs. Urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC), the major subgroup of ExPEC, are among the most prevalent microbial diseases world wide and a substantial burden for public health care systems. UTIs are responsible for serious morbidity and mortality in the elderly, in young children, and in immune-compromised and hospitalized patients. ExPEC strains are different, both from genetic and clinical perspectives, from commensal E. coli strains belonging to the normal intestinal flora and from intestinal pathogenic E. coli strains causing diarrhea. ExPEC strains are characterized by a broad range of alternate virulence factors, such as adhesins, toxins, and iron accumulation systems. Unlike diarrheagenic E. coli, whose distinctive virulence determinants evoke characteristic diarrheagenic symptoms and signs, ExPEC strains are exceedingly heterogeneous and are known to possess no specific virulence factors or a set of factors, which are obligatory for the infection of a certain extraintestinal site (e. g. the urinary tract). The ExPEC genomes are highly diverse mosaic structures in permanent flux. These strains have obtained a significant amount of DNA (predictably up to 25% of the genomes) through acquisition of foreign DNA from diverse related or non-related donor species by lateral transfer of mobile genetic elements, including pathogenicity islands (PAIs), plasmids, phages, transposons, and insertion elements. The ability of ExPEC strains to cause disease is mainly derived from this horizontally acquired gene pool; the extragenous DNA facilitates rapid adaptation of the pathogen to changing conditions and hence the extent of the spectrum of sites that can be infected. However, neither the amount of unique DNA in different ExPEC strains (or UPEC strains) nor the mechanisms lying behind the observed genomic mobility are known. Due to this extreme heterogeneity of the UPEC and ExPEC populations in general, the routine surveillance of ExPEC is exceedingly difficult. In this project, we presented a novel virulence gene algorithm (VGA) for the estimation of the extraintestinal virulence potential (VP, pathogenicity risk) of clinically relevant ExPECs and fecal E. coli isolates. The VGA was based on a DNA microarray specific for the ExPEC phenotype (ExPEC pathoarray). This array contained 77 DNA probes homologous with known (e.g. adhesion factors, iron accumulation systems, and toxins) and putative (e.g. genes predictably involved in adhesion, iron uptake, or in metabolic functions) ExPEC virulence determinants. In total, 25 of DNA probes homologous with known virulence factors and 36 of DNA probes representing putative extraintestinal virulence determinants were found at significantly higher frequency in virulent ExPEC isolates than in commensal E. coli strains. We showed that the ExPEC pathoarray and the VGA could be readily used for the differentiation of highly virulent ExPECs both from less virulent ExPEC clones and from commensal E. coli strains as well. Implementing the VGA in a group of unknown ExPECs (n=53) and fecal E. coli isolates (n=37), 83% of strains were correctly identified as extraintestinal virulent or commensal E. coli. Conversely, 15% of clinical ExPECs and 19% of fecal E. coli strains failed to raster into their respective pathogenic and non-pathogenic groups. Clinical data and virulence gene profiles of these strains warranted the estimated VPs; UPEC strains with atypically low risk-ratios were largely isolated from patients with certain medical history, including diabetes mellitus or catheterization, or from elderly patients. In addition, fecal E. coli strains with VPs characteristic for ExPEC were shown to represent the diagnostically important fraction of resident strains of the gut flora with a high potential of causing extraintestinal infections. Interestingly, a large fraction of DNA probes associated with the ExPEC phenotype corresponded to novel DNA sequences without any known function in UTIs and thus represented new genetic markers for the extraintestinal virulence. These DNA probes included unknown DNA sequences originating from the genomic subtractions of four clinical ExPEC isolates as well as from five novel cosmid sequences identified in the UPEC strains HE300 and JS299. The characterized cosmid sequences (pJS332, pJS448, pJS666, pJS700, and pJS706) revealed complex modular DNA structures with known and unknown DNA fragments arranged in a puzzle-like manner and integrated into the common E. coli genomic backbone. Furthermore, cosmid pJS332 of the UPEC strain HE300, which carried a chromosomal virulence gene cluster (iroBCDEN) encoding the salmochelin siderophore system, was shown to be part of a transmissible plasmid of Salmonella enterica. Taken together, the results of this project pointed towards the assumptions that first, (i) homologous recombination, even within coding genes, contributes to the observed mosaicism of ExPEC genomes and secondly, (ii) besides en block transfer of large DNA regions (e.g. chromosomal PAIs) also rearrangements of small DNA modules provide a means of genomic plasticity. The data presented in this project supplemented previous whole genome sequencing projects of E. coli and indicated that each E. coli genome displays a unique assemblage of individual mosaic structures, which enable these strains to successfully colonize and infect different anatomical sites.

Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM ( approximately prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion ( approximately 3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.

Determinants of online sperm donor success: How women choose

Because the worldwide demand for sperm donors is much higher than the actual supply available through fertility clinics, an informal online market has emerged for sperm donation. Very little empirical evidence exists, however, on this newly formed market and even less on the characteristics that lead to donor success. This article therefore explores the determinants of online sperm donors’ selection success, which leads to the production of offspring via informal donation. We find that donor age and income play a significant role in donor success as measured by the number of times selected, even though there is no requirement for ongoing paternal investment. Donors with less extroverted and lively personality traits who are more intellectual, shy and systematic are more successful in realizing offspring via informal donation. These results contribute to both the economic literature on human behaviour and on large-scale decision-making.

Anion directed template synthesis of Cu(II) complexes of a N,N,O donor mono-condensed Schiff base ligand: A molecular scaffold forming highly ordered H-bonded rectangular grids

Anion directed, template syntheses of two dinuclear copper(II) complexes of mono-condensed Schiff base ligand Hdipn (4-[(3-aminopentylimino)-methyl]-benzene-1,3-diol) involving 2,4- dihydroxybenzaldehyde and 1,3-diaminopentane were realized in the presence of bridging azide and acetate anions. Both complexes, [Cu-2(dipn)(2)(N-3)(2)] (1) and [Cu-2(dip(n))(2)(OAc)(2)] (2) have been characterized by X-ray crystallography. The two mononuclear units are joined together by basal-apical, double end-on azido bridges in complex 1 and by basal-apical, double mono-atomic acetate oxygen-bridges in 2. Both complexes form rectangular grid-like supramolecular structures via H-bonds connecting the azide or acetate anion and the p-hydroxy group of 2,4- dihydroxybenzaldehyde. Variable-temperature (300-2 K) magnetic susceptibility measurements reveal that complex 1 has antiferromagnetic coupling (J = -2.10 cm (1)) through the azide bridge while 2 has intra-dimer ferromagnetic coupling through the acetate bridge and inter-dimer antiferromagnetic coupling through H-bonds (J = 2.85 cm (1), J' = -1.08 cm (1)). (C) 2009 Elsevier B. V. All rights reserved.

Two-Step Folding of Donor-Acceptor Foldamers

In a series of polymers containing alternately placed electron-rich dialkoxyilaphthalene (DAN) donors and electron-deficient pyromellitic diimide (PDI) acceptors linked by hexa(oxyethylene) (OE-6) segments, the ability to form a folded D-A stack was intentionally disrupted by random inclusion of varying amounts of a comonomer that is devoid of DAN donor units. NMR spectroscopic studies of folding in these copolymers, induced by NH4SCN that coordinates with the OE-6 segments and facilitates the charge-transfer (C-T) induced D-A stacking, clearly reveals the presence of PDI units that are isolated and those that are located at the ends of (D-A),, stacks. Similar conclusions regarding the presence of stacked and unstacked regions along the polymer chain were also inferred from UV-vis spectroscopic studies that probe the evolution of charge-transfer band. One fascinating aspect of these copolymers wits their ability to undergo it two-step folding: first, short (D-A),, stacks are formed by the interaction of the NH4+ ion with some specific regions of the polymer chain, and subsequently these Stacks are further stacked via a two-point interaction with it suitably designed external folding agent that carries a DAN unit and all ammonium group. In the second step, the interaction first occurs by the coordination of the ammonium group of the folding agent with the OE-6 segment, which in turn facilitates the C-T interaction of the DAN unit with the adjacent uncomplexed PDI units along the polymer chain, leading to an increase ill the slacking. Variations of several spectral features, during both UV-vis and NMR spectroscopic titrations, clearly reveal this novel two-step folding process.

Cow's milk allergy and the development of tolerance

Aims: To gain insight on the immunological processes behind cow’s milk allergy (CMA) and the development of oral tolerance. To furthermore investigate the associations of HLA II and filaggrin genotypes with humoral responses to early oral antigens. Methods: The study population was from a cohort of 6209 healthy, full-term infants who in a double-blind randomized trial received supplementary feeding at maternity hospitals (mean duration 4 days): cow’s milk (CM) formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed CM associated symptoms that subsided during elimination diet (n=223) underwent an open oral CM challenge (at mean age 7 months). The challenge was negative in 112, and in 111 it confirmed CMA, which was IgE-mediated in 83. Patients with CMA were followed until recovery, and 94 of them participated in a follow-up study at age 8-9 years. We investigated serum samples at diagnosis (mean age 7 months, n=111), one year later (19 months, n=101) and at follow-up (8.6 years, n=85). At follow-up, also 76 children randomly selected from the original cohort and without CM associated symptoms were included. We measured CM specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin, α-casein and ovalbumin specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay in sera. We applied a microarray based immunoassay to measure the binding of IgE, IgG4 and IgA serum antibodies to sequential epitopes derived from five major CM proteins at the three time points in 11 patients with active IgE-mediated CMA at age 8-9 years and in 12 patients who had recovered from IgE-mediated CMA by age 3 years. We used bioinformatic methods to analyze the microarray data. We studied T cell expression profile in peripheral blood mononuclear cell (PBMC) samples from 57 children aged 5-12 years (median 8.3): 16 with active CMA, 20 who had recovered from CMA by age 3 years, 21 non-atopic control subjects. Following in vitro β-lactoglobulin stimulation, we measured the mRNA expression in PBMCs of 12 T-cell markers (T-bet, GATA-3, IFN-γ, CTLA4, IL-10, IL-16, TGF-β, FOXP3, Nfat-C2, TIM3, TIM4, STIM-1) with quantitative real time polymerase chain reaction, and the protein expression of CD4, CD25, CD127, FoxP3 with flow cytometry. To optimally distinguish the three study groups, we performed artificial neural networks with exhaustive search for all marker combinations. For genetic associations with specific humoral responses, we analyzed 14 HLA class II haplotypes, the PTPN22 1858 SNP (R620W allele) and 5 known filaggrin null mutations from blood samples of 87 patients with CMA and 76 control subjects (age 8.0-9.3 years). Results: High IgG and IgG4 levels to β-lactoglobulin and α-casein were associated with the HLA (DR15)-DQB1*0602 haplotype in patients with CMA, but not in control subjects. Conversely, (DR1/10)-DQB1*0501 was associated with lower IgG and IgG4 levels to these CM antigens, and to ovalbumin, most significantly among control subjects. Infants with IgE-mediated CMA had lower β -lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p<0.05) at diagnosis than infants with non-IgE-mediated CMA or control subjects. When CMA persisted beyond age 8 years, CM specific IgE levels were higher at all three time points investigated and IgE epitope binding pattern remained stable (p<0.001) compared with recovery from CMA by age 3 years. Patients with persisting CMA at 8-9 years had lower serum IgA levels to β-lactoglobulin at diagnosis (p=0.01), and lower IgG4 levels to β-lactoglobulin (p=0.04) and α-casein (p=0.05) at follow-up compared with patients who recovered by age 3 years. In early recovery, signal of IgG4 epitope binding increased while that of IgE decreased over time, and binding patterns of IgE and IgG4 overlapped. In T cell expression profile in response to β –lactoglobulin, the combination of markers FoxP3, Nfat-C2, IL-16, GATA-3 distinguished patients with persisting CMA most accurately from patients who had become tolerant and from non-atopic subjects. FoxP3 expression at both RNA and protein level was higher in children with CMA compared with non-atopic children. Conclusions: Genetic factors (the HLA II genotype) are associated with humoral responses to early food allergens. High CM specific IgE levels predict persistence of CMA. Development of tolerance is associated with higher specific IgA and IgG4 levels and lower specific IgE levels, with decreased CM epitope binding by IgE and concurrent increase in corresponding epitope binding by IgG4. Both Th2 and Treg pathways are activated upon CM antigen stimulation in patients with CMA. In the clinical management of CMA, HLA II or filaggrin genotyping are not applicable, whereas the measurement of CM specific antibodies may assist in estimating the prognosis.

Synthesis and Characterization of a Class of Donor-Acceptor Conjugated Molecules: Experiments and Theoretical Calculations

A class of conjugated molecules containing donor (thiophene) and acceptor (malononitrile) is synthesized by Knoevenagel condensation reaction between 2-(2,6-dimethy1-4H-pyran-4-ylidene) malononitrile and thiophene carbaldehyde containing two and three thiophene units. The resulting molecules are characterized by H-1 and C-13 NMR. We have performed UV-vis absorption, fluorescence, and cyclic voltammetry measurements on these materials. The spectroscopic and electrochemical measurements proved beyond doubt that these materials possess lowexcitation gap and are suitable for being an active material in various electronic devices. We have also performed electronic structure calculations using density functional theory (DFT) and INDO/SCI methods to characterize the ground and excited states of this class of molecules. These donor-acceptor molecules show a strong charge transfercharacter that increases with the increase in the number of thiophene rings coupled to the malononitrile acceptor moiety. We have also calculated the pi-coherence length, Stoke's shift, and effect of solvents on excited states for this class of molecules, Our theoretical values agree well with experimental results.

Spectroscopic studies of n-donor-σ-acceptor systems: pyridines

The Charge-transfer equilibria of a number of substituted pyridines with iodine have been investigated. Solvent effects on the charge-transfer equilibrium of the pyridineiodine system have been examined. Hydrogen bonding data of substituted pyridines with phenol have been reported.

Spectroscopic studies of n-donor - σ-acceptor systems: Carbonyl and thiocarbonyl compounds as donors

The interaction of ketones and various thiocarbonyl derivatives with iodine has been examined. The thermodynamics of the interaction of carbonyl and thiocarbonyl donors have been discussed and compared.

Spectroscopic studies of the donor properties of triphenyl-amine, -phosphine, -arsine and -stibine interaction with iodine and phenol

The interaction of iodine with triphenylamine ,tripheny lphosphine, triphenylarsine and triphenystibine has been investigated by electronic spectroscopy. Transformation of the outer charge-transfer complexes to the inner complexes (quarternary salts) has been examined. The relations of the ionization potentials of the donors with the hvc.t have been discussed and various c.t. parameters have been estimated. Hydrogen bonding of these donors with phenol have been reported.