Design and synthesis of inhibitors of DC-sign mediated infections

DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Nonintegrin) is a C-type (Calcium dependent) lectin, expressed as homotetramers (presenting four copies of a Carbohydrate Recognition Domain (CRD) at the C-terminus) on the surface of immature Dendritic Cells. [1] Dendritic Cells (DCs) areone of the most important class of Antigen Presenting Cells (APCs). They recognize many pathogens through various receptors such as DC-SIGN. After recognition, the pathogen is internalized and DCs mature and migrate to lymph nodes.[2] Then, DCs relay the corresponding processing antigens as MHC complexes to naive T-cells, which differentiate allowing the appropriate immuno-reponse. Some of these pathogens, such as HIV, hijack this mechanism to infect the immune system: they are recognized by DCs but escape the processing pathway. Thus, they can remain “hidden” inside the dendritic cells for many days, being able to reach and infect their target T-cells. The main carbohydrate ligand recognized by DC-SIGN is the high mannose glycan (Man)9(GlcNAc)2 , also known as Man9, a branched oligosaccharide which is presented in multiple copies by several pathogen glycoproteins (gp120, GP1, …). Hence, multivalent mannose display should be an adequate strategy to interact with this lectin with high affinity. In vivo, mannosides are normally hydrolyzed by mannosidases: the use of a structural mimic in place of the natural sugar could avoid an easy degradation in a biological environment. The aim of this project is to design and prepare products that meet these requirements. So far we have demonstrated that the monovalent mimic 1 shown in Figure 1[3] interacts with DC-SIGN (using NMR) and inhibits the DC-SIGN mediated infection in a pseudo-typed Ebola virus model. Moreover, this molecule has been conjugated to a Boltorn-type, leading to neo-glycoconjugates that inhibit the binding of DC-SIGN to gp120 (envelope protein of HIV). In this communication we will report the synthesis of new monovalent inhibitors and the results of their binding assays by SPR. We will show also the synthesis of some multivalent compounds. Acknowledgments. This work was supported by Azioni Integrate Italia-Spagna (IT074ABCCM). [1] T. B. H. Geijtenbeek, , Y. van Kook, et al., Cell 2000, 100, 575-585. [2] Y. van Kooyk, T. B. H. Geijtenbeek, Nat. Rev. Immunol. 2003, 3, 697-709. [3] José J. Reina, Sara Sattin, Donatella Invernizzi, Silvia Mari, Lorena Martínez-Prats, Georges Tabarani, Franck Fieschi, Rafael Delgado, Pedro M. Nieto, Javier Rojo, Anna Bernardi, ChemMedChem , 2007, 2(7),1030-1036

The roles of transparency and trust in the relationship between corruption and citizen satisfaction

Reducing corruption and improving citizen satisfaction are important aims of government, yet the link between these two policy aims has rarely been explored. This article reports a study into the roles played by transparency and trust in the relationship between governmental corruption and citizen satisfaction with public services. The study was based on data gathered in South Korea to evaluate a specific initiative that had sought to reduce corruption and increase citizen satisfaction with public works programmes. The data indicated that the relationship between corruption and satisfaction was moderated by transparency and partially mediated by trust. Points for practitioners: The study sheds light on the roles of transparency and trust in the relationship between corruption and citizen satisfaction with public services, and thus provides insights for developing policy aimed at curtailing corruption and improving satisfaction

Deeply Virtual Compton Scattering off the neutron

The present experiment exploits the interference between the Deeply Virtual Compton Scattering (DVCS) and the Bethe-Heitler processes to extract the imaginary part of DVCS amplitudes on the neutron and on the deuteron from the helicity-dependent D$({\vec e},e'\gamma)X$ cross section measured at $Q^2$=1.9 GeV$^2$ and $x_B$=0.36. We extract a linear combination of generalized parton distributions (GPDs) particularly sensitive to $E_q$, the least constrained GPD. A model dependent constraint on the contribution of the up and down quarks to the nucleon spin is deduced.Comment: Published in Phys. Rev. Let

Scaling Tests of the Cross Section for Deeply Virtual Compton Scattering

We present the first measurements of the \vec{e}p->epg cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region. The Q^2 dependence (from 1.5 to 2.3 GeV^2) of the helicity-dependent cross section indicates the twist-2 dominance of DVCS, proving that generalized parton distributions (GPDs) are accessible to experiment at moderate Q^2. The helicity-independent cross section is also measured at Q^2=2.3 GeV^2. We present the first model-independent measurement of linear combinations of GPDs and GPD integrals up to the twist-3 approximation.Comment: 5 pages, 4 figures, 2 tables. Text shortened for publication. References added. One figure remove

The E00-110 experiment in Jefferson Lab's Hall A: Deeply Virtual Compton Scattering off the Proton at 6 GeV

We present final results on the photon electroproduction ($\vec{e}p\rightarrow ep\gamma$) cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region from Jefferson Lab experiment E00-110. Results from an analysis of a subset of these data were published before, but the analysis has been improved which is described here at length, together with details on the experimental setup. Furthermore, additional data have been analyzed resulting in photon electroproduction cross sections at new kinematic settings, for a total of 588 experimental bins. Results of the $Q^2$- and $x_B$-dependences of both the helicity-dependent and helicity-independent cross sections are discussed. The $Q^2$-dependence illustrates the dominance of the twist-2 handbag amplitude in the kinematics of the experiment, as previously noted. Thanks to the excellent accuracy of this high luminosity experiment, it becomes clear that the unpolarized cross section shows a significant deviation from the Bethe-Heitler process in our kinematics, compatible with a large contribution from the leading twist-2 DVCS$^2$ term to the photon electroproduction cross section. The necessity to include higher-twist corrections in order to fully reproduce the shape of the data is also discussed. The DVCS cross sections in this paper represent the final set of experimental results from E00-110, superseding the previous publication.Comment: 48 pages, 32 figure

Exclusive Neutral Pion Electroproduction in the Deeply Virtual Regime

We present measurements of the ep->ep pi^0 cross section extracted at two values of four-momentum transfer Q^2=1.9 GeV^2 and Q^2=2.3 GeV^2 at Jefferson Lab Hall A. The kinematic range allows to study the evolution of the extracted hadronic tensor as a function of Q^2 and W. Results will be confronted with Regge inspired calculations and GPD predictions. An intepretation of our data within the framework of semi-inclusive deep inelastic scattering has also been attempted

Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)–induced gamma-activating factor–mediated immunity and interferon alpha (IFNA)–induced interferon-stimulated genes factor 3–mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor–mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3–mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding

Computer-aided DSM-IV-diagnostics – acceptance, use and perceived usefulness in relation to users' learning styles

BACKGROUND: CDSS (computerized decision support system) for medical diagnostics have been studied for long. This study was undertaken to investigate how different preferences of Learning Styles (LS) of psychiatrists might affect acceptance, use and perceived usefulness of a CDSS for diagnostics in psychiatry. METHODS: 49 psychiatrists (specialists and non-specialists) from 3 different clinics volunteered to participate in this study and to use the CDSS to diagnose a paper-based case (based on a real patient). LS, attitudes to CDSS and complementary data were obtained via questionnaires and interviews. To facilitate the study, a special version of the CDSS was created, which automatically could log interaction details. RESULTS: The LS preferences (according to Kolb) of the 49 physicians turned out as follows: 37% were Assimilating, 31% Converging, 27% Accommodating and 6% Diverging. The CDSS under study seemed to favor psychiatrists with abstract conceptualization information perceiving mode (Assimilating and Converging learning styles). A correlation between learning styles preferences and computer skill was found. Positive attitude to computer-aided diagnostics and learning styles preferences was also found to correlate. Using the CDSS, the specialists produced only 1 correct diagnosis and the non-specialists 2 correct diagnoses (median values) as compared to the three predetermined correct diagnoses of the actual case. Only 10% had all three diagnoses correct, 41 % two correct, 47 % one correct and 2 % had no correct diagnose at all. CONCLUSION: Our results indicate that the use of CDSS does not guarantee correct diagnosis and that LS might influence the results. Future research should focus on the possibility to create systems open to individuals with different LS preferences and possibility to create CDSS adapted to the level of expertise of the user

IL-12 RB1 Genetic Variants Contribute to Human Susceptibility to Severe Acute Respiratory Syndrome Infection among Chinese

BACKGROUND: Cytokines play important roles in antiviral action. We examined whether polymorphisms of interleukin (IL)-12 receptor B1 (IL-12RB1) affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS). METHODS: A case-control study was carried out in Chinese SARS patients and healthy controls. The genotypes of 4SNPs on IL-12 RB1 gene, +705A/G,+1158T/C, +1196G/C and +1664 C/T, were determined by PCR-RFLP. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. RESULTS: Comparison between patients and close contacts showed that individuals with the +1664 C/T (CT and TT) genotype had a 2.09-fold (95% confidence interval [CI], 1.90-7.16) and 2.34-fold (95% CI, 1.79-13.37) increased risk of developing SARS, respectively. For any of the other three polymorphisms, however, no significant difference can be detected in allele or genotype frequencies between patients and controls. Additionally, estimation of the frequencies of multiple-locus haplotypes revealed potential risk haplotypes (GCCT) for SARS infection. CONCLUSIONS: Our data indicate that genetic variants of IL12RB1confer genetic susceptibility to SARS infection, but not necessary associated with the progression of the disease in Chinese population

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways