Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

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Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

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Enriching the biological space of natural products and charting drug metabolites,through real time biotransformation monitoring: The NMR tube bioreactor

Background

Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps.

Immune network behavior—I. From stationary states to limit cycle oscilations

We develop a model for the idiotypic interaction between two B cell clones. This model takes into account B cell proliferation, B cell maturation, antibody production, the formation and subsequent elimination of antibody-antibody complexes and recirculation of antibodies between the spleen and the blood. Here we investigate, by means of stability and bifurcation analysis, how each of the processes influences the model's behavior. After appropriate nondimensinalization, the model consists of eight ordinary differential equations and a number of parameters. We estimate the parameters from experimental sources. Using a coordinate system that exploits the pairwise symmetry of the interactions between two clones, we analyse two simplified forms of the model and obtain bifurcation diagrams showing how their five equilibrium states are related. We show that the so-called immune states lose stability if B cell and antibody concentrations change on different time scales. Additionally, we derive the structure of stable and unstable manifolds of saddle-tye equilibria, pinpoint their (global) bifurcations and show that these bifurcations play a crucial role in determining the parameter regimes in which the model exhibits oscillatory behavior.     

Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists

The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure–activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.     

Truncation of a P1 leader proteinase facilitates potyvirus replication in a non‐permissive host

The Potyviridae family is a major group of plant viruses that includes c. 200 species, most of which have narrow host ranges. The potyvirid P1 leader proteinase self‐cleaves from the remainder of the viral polyprotein and shows large sequence variability linked to host adaptation. P1 proteins can be classified as Type A or Type B on the basis, amongst other things, of their dependence or not on a host factor to develop their protease activity. In this work, we studied Type A proteases from the Potyviridae family, characterizing their host factor requirements. Our in vitro cleavage analyses of potyvirid P1 proteases showed that the N‐terminal domain is relevant for host factor interaction and suggested that the C‐terminal domain is also involved. In the absence of plant factors, the N‐terminal end of Plum pox virus P1 antagonizes protease self‐processing. We performed extended deletion mutagenesis analysis to define the N‐terminal antagonistic domain of P1. In viral infections, removal of the P1 protease antagonistic domain led to a gain‐of‐function phenotype, strongly increasing local infection in a non‐permissive host. Altogether, our results shed new insights into the adaptation and evolution of potyvirids.     

Design, synthesis and catalytic activity of a serine protease synthetic model

The design, synthesis and catalytic properties of acyclic branched peptide carrier that possesses thecatalytic triad residues of the serine proteases isreported. The synthesis of the peptide model wastotally completed on solid support using threedifferent orthogonal amino protecting groups.Hydrolytic activity measurements againstSuc-Ala-Ala-Ala-pNA substrate showed that it ishydrolysed by the peptide model to a small extent.Despite this small hydrolytic activity, it is thefirst time, to our knowledge, that hydrolysis of such a substrate is reported by an enzyme model compound.Contrary, this enzyme model peptide showedconsiderable activity against the Boc-Ala-pNPsubstrate (k_cat = 0.414 min^–1 and K_m = 0.228 mm). These results suggest that thedesigned carrier brings in appropriate contact thecatalytic triad residues (Ser, His, Asp) resulting inthe obtained hydrolytic activity.     

Biodegradable films made from low density polyethylene (LDPE), wheat starch and soluble starch for food packaging applications. Part 2

Blends of LDPE and wheat or soluble starch were extruded, hot pressed and studied, after conditioning at various relative humidities, with regard to their mechanical properties and gas/water permeabilities before and after storage. Several theoretical and semiempirical calculations for mechanical properties and gas permeability are applied and possible interpretations are provided for occasionally observed deviations between the experimental and the theoretical values. Some of the semiempirical models predicted reasonably well the mechanical behaviour of the films. The presence of starch, at contents >30%, had an adverse effect on the mechanical properties of LDPE/starch blends. The degradability of several LDPE/starch blends and the accompanying changes in their mechanical properties are also assessed. Gas permeability and water vapour transmission rate increased proportionally with the starch content in the blend.     

Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used

Background

The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient’s distribution in relation to the questionnaire used.

Methods

136 COPD patients (58±21% FEV₁ predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis.

Results

GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d^-1, p <0.001) in both the low and high risk quadrants.

Conclusions

Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion.

Clinical Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01388218","term_id":"NCT01388218"}}NCT01388218