Harnessing conformational drivers in drug design.

This review article explores the pivotal role of conformational drivers in the discovery of drug-like molecules and illustrates their significance through real-life examples. Understanding molecular conformation is paramount to drug hunting as it can impact on- and off-target potency, metabolism, permeability, and solubility. Each conformational driver or effector is described and exemplified in a separate section.

Summary of five years of operation of the out-of-court system for pursuing patient claims in Poland - a retrospective analysis of applications for evaluating medical events.

Objective: Providing health services involves a risk of medical events and adverse events. The transparency and quality of the healthcare system have a direct impact on patient's safety. One of the measures of the quality of health services is monitoring and reporting these irregularities, as well as analysing the causes of their occurrence.

Fluorine NMR study of proline-rich sequences using fluoroprolines.

Proline homopolymer motifs are found in many proteins; their peculiar conformational and dynamic properties are often directly involved in those proteins' functions. However, the dynamics of proline homopolymers is hard to study by NMR due to a lack of amide protons and small chemical shift dispersion. Exploiting the spectroscopic properties of fluorinated prolines opens interesting perspectives to address these issues.

Synthesis and Conformational Properties of 3,4-Difluoro-l-prolines.

Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/ trans isomerization) are introduced. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry.

IL-10 Receptor or TGF-β Neutralization Abrogates the Protective Effect of a Specific Nondigestible Oligosaccharide Mixture in Cow-Milk-Allergic Mice.

Background: Dietary nondigestible, short-chain galacto-, long-chain fructo-, and pectin-derived acidic oligosaccharides (GFAs) lower the effector response in cow-milk-allergic (CMA) mice; and forkhead box P3 (Foxp3)-positive regulatory T cells (Tregs) were shown to contribute to this.

Objective: The aim of this study was to assess the contribution of interleukin 10 (IL-10) and transforming growth factor β (TGF-β) to the protective effect of the GFA diet in CMA mice.

Methods: Female C3H/HeOuJ mice, 3-4 wk old, were orally sensitized with cholera toxin (Sham) or whey and cholera toxin (Whey) 1 time/wk for 5 consecutive weeks and challenged with whey 1 wk later.

Minimising conformational bias in fluoroprolines through vicinal difluorination.

Monofluorination at the proline 4-position results in conformational effects, which is exploited for a range of applications. However, this conformational distortion is a hindrance when the natural proline conformation is important. Here we introduce (3S,4R)-3,4-difluoroproline, in which the individual fluorine atoms instil opposite conformational effects, as a suitable probe for fluorine NMR studies.

Dietary, nondigestible oligosaccharides and M-16V suppress allergic inflammation in intestine via targeting dendritic cell maturation.

Dietary intervention with short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and M-16V () (GF/) suppresses food allergic symptoms in mice, potentially via intestinal epithelial cell (IEC)-derived galectin-9. Furthermore, in vitro studies showed galacto- and fructo-oligosaccharides (GF) to enhance the immunomodulatory capacity of a TLR9 ligand representing bacterial CpG DNA when exposed to IEC. In this study, we investigated whether GF/ modulates dendritic cells (DCs) and subsequent Th2 and regulatory T cell (T) frequency in the small intestinal lamina propria (SI-LP).

A Specific Mixture of Fructo-Oligosaccharides and M-16V Facilitates Partial Non-Responsiveness to Whey Protein in Mice Orally Exposed to β-Lactoglobulin-Derived Peptides.

Oral tolerance is a promising approach for allergy prevention in early life, but it strongly depends on allergen exposure and proper immune environment. Small tolerance-inducing peptides and dietary immunomodulatory components may comprise an attractive method for allergy prevention in at-risk infants. This study aimed to investigate whether early oral exposure to β-lactoglobulin-derived peptides (BLG-peptides) and a specific synbiotic mixture of short- and long- chain fructo-oligosaccharides (scFOS/lcFOS, FF) and () M-16V (FF/) can prevent cow's milk allergy (CMA).

Simulating the environmental performance of post-harvest management measures to comply with the EU Nitrates Directive.

Nitrate (NO) leaching from farmland remains the predominant source of nitrogen (N) loads to European ground- and surface water. As soil mineral N content at harvest is often high and may increase by mineralisation from crop residues and soil organic matter, it is critical to understand which post-harvest management measures can be taken to restrict the average NO concentration in ground- and surface waters below the norm of 50 mg l. Nitrate leaching was simulated with the EU-rotate_N model on a silty and a sandy soil following the five main arable crops cultivated in Flanders: cut grassland, silage maize, potatoes, sugar beets and winter wheat, in scenarios of optimum fertilisation with and without post-harvest measures.

Non-digestible oligosaccharides modulate intestinal immune activation and suppress cow's milk allergic symptoms.

Background: Cow's milk allergy is a common food allergy in childhood and no effective preventive or curative treatment is available. This study aimed at comparing single short-chain galacto- (scGOS), long-chain fructo- (lcFOS) or pectin-derived acidic oligosaccharides (pAOS) and/or mixtures of scGOS/lcFOS (GF) or scGOS/lcFOS/pAOS (GFA) to prevent or treat food allergy.

Methods: In the preventive protocol, C3H/HeOuJ mice were fed diets containing single oligosaccharides or mixtures GF or GFA throughout the study protocol.

DHA-rich tuna oil effectively suppresses allergic symptoms in mice allergic to whey or peanut.

Background: Supplementation with long-chain n-3 polyunsaturated fatty acids (LCPUFAs) has been found to reduce the development of allergic disease.

Objective: The aim of this study was to compare the effectiveness of fish oil diets rich in eicosapentaenoic acid (20:5n-3; EPA) or docosahexaenoic acid (22:6n-3; DHA) in suppressing food allergic symptoms.

Methods: Mice were fed a control diet (10% soybean oil) or fish oil diet rich in EPA (4% soybean oil + 6% EPA oil containing 28.

CD25+ regulatory T cells transfer n-3 long chain polyunsaturated fatty acids-induced tolerance in mice allergic to cow's milk protein.

Background: Recently, we have shown that dietary long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) largely prevent allergic sensitization in a murine model for cow's milk allergy. The aim of this study was to assess the contribution of regulatory T cells (Treg) in the prevention of food allergy by n-3 LCPUFA.

Methods: C3H/HeOuJ female donor mice were fed a control or fish oil diet before and during oral sensitization with cow's milk protein whey.

Alterations in regulatory T cells induced by specific oligosaccharides improve vaccine responsiveness in mice.

Unlabelled: Prophylactic vaccinations are generally performed to protect naïve individuals with or without suppressed immune responsiveness. In a mouse model for Influenza vaccinations the specific alterations of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) in the immune modulation induced by orally supplied oligosaccharides containing scGOS/lcFOS/pAOS was assessed. This dietary intervention increased vaccine specific DTH responses.

Mitigation options to reduce phosphorus losses from the agricultural sector and improve surface water quality: a review.

The EU Water Framework Directive (WFD) obliges Member States to improve the quality of surface water and groundwater. The measures implemented to date have reduced the contribution of point sources of pollution, and hence diffuse pollution from agriculture has become more important. In many catchments the water quality remains poor.

Oral treatment with β-lactoglobulin peptides prevents clinical symptoms in a mouse model for cow's milk allergy.

Background: Prior exposure to partial whey hydrolysates has been shown to reduce the allergic response to whey in mice. This effect was more pronounced in combination with a diet containing non-digestible oligosaccharides (scGOS/lcFOS/pAOS). It is unknown which fractions/epitopes are responsible for this effect.

Dietary long chain n-3 polyunsaturated fatty acids prevent allergic sensitization to cow's milk protein in mice.

Background: Cow's milk allergy is one of the most common food allergies in children and no treatment is available. Dietary lipid composition may affect the susceptibility to develop allergic disease.

Objective: Assess whether dietary supplementation with long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) prevents the establishment of food allergy.

Use of a driving simulator to assess performance under adverse weather conditions in adults with albinism.

Participants with albinism have reduced vision and nystagmus with reduced foveation times. This prospective study evaluated driving in 12 participants with albinism and 12 matched controls. Participants drove a vehicle simulator through a virtual rural course in sunny and foggy conditions.

Invariant natural killer T cells contribute to the allergic response in cow's milk protein-sensitized mice.

Background: Little is known about the contribution of the invariant natural killer T (iNKT) cells in the onset of food allergy. Using a mouse model for cow's milk allergy the function of iNKT cells was investigated.

Methods: Mice were sensitized orally with casein or whey proteins.

Oral tolerance induction by partially hydrolyzed whey protein in mice is associated with enhanced numbers of Foxp3+ regulatory T-cells in the mesenteric lymph nodes.

Background: Hypoallergenic formulas are considered a good option for infants at risk for cow's milk allergy. The aim of this animal study was to investigate whether whey hydrolyzates (WH) have the capacity to induce oral tolerance to whey.

Methods: Whey, partial or extensive WH was given via gavages to naïve mice prior to oral whey sensitization using cholera toxin as an adjuvant.

A potential role for CD25+ regulatory T-cells in the protection against casein allergy by dietary non-digestible carbohydrates.

Dietary non-digestible carbohydrates reduce the development of cows' milk allergy in mice. In the present study, the contribution of CD25+ regulatory T-cells (Treg) was investigated using in vivo Treg depletion and adoptive transfer studies. Mice were orally sensitised with casein and fed a diet containing 2 % short-chain galacto-, long-chain fructo- and acidic oligosaccharides (GFA) or a control diet.

Dietary fatty acids affect the immune system in male mice sensitized to ovalbumin or vaccinated with influenza.

PUFA are precursor molecules for eicosanoids such as leukotrienes and prostaglandins and may influence immune function through other mechanisms involving membranes, cell signaling, and gene expression. Immune-modulating properties of diets containing different oils [sunflower oil, rich in linoleic acid; linseed oil, rich in α-linolenic acid; salmon oil, rich in marine (n-3) PUFA; and beef tallow, rich in SFA] were investigated in an influenza-vaccination model, in which the delayed-type hypersensitivity (DTH) response was studied in C57BL/6 mice, and an ovalbumin (OVA)-sensitization model for experimental allergy in BALB/c mice. Six-week-old mice were fed the different diets for 7 wk.

Contribution of IgE and immunoglobulin free light chain in the allergic reaction to cow's milk proteins.

Background: Cow's milk allergy (CMA) affects 2.5% of young infants. In previous murine studies it was observed that allergic sensitization to the major cow's milk allergens casein and whey led, respectively, to IgE-independent and IgE-dependent clinical responses.

Depletion of CD4+CD25+ T cells switches the whey-allergic response from immunoglobulin E- to immunoglobulin free light chain-dependent.

Background: Symptoms of allergy are largely attributed to an IgE-mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig-free light chains (IgLC) may act as an alternate mechanism to induce allergic responses.