IgG from Adult Atopic Dermatitis (AD) Patients Induces Thymic IL-22 Production and CLA Expression on CD4+ T Cells: Possible Epigenetic Implications Mediated by miRNA

Atopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD patients could modulate the thymic maturation of IL-22-producing T cells and CLA+ T cells of non-atopic infants. Given that miRNAs regulate immune response genes, we evaluated whether miRNA expression is also altered in cultured thymocytes. Thymocytes were cultured with purified IgG from AD patients or control conditions (mock, Intravenous-IgG (IVIg), non-atopic IgG, or atopic non-AD IgG). Using flow cytometry analysis, we assessed the expression of CLA and intracellular levels of IL-4, IFN-γ, and IL-22 on double-positive T cells (DP T), CD4 T cells, or CD8 T cells. We also investigated the frequency of IgG isotypes and their direct interaction with the thymic T cells membrane. The miRNA profiles were evaluated by the Illumina small RNA-seq approach. MiRNA target gene prediction and enrichment analyses were performed using bioinformatics. Increased frequencies of IL-22 and CLA+ producing CD4+ T cells cultured with IgG of AD patients was seen in non-atopic infant thymocytes compared to all control conditions. No alterations were observed in the frequency of IgG isotypes among evaluated IgG pools. Evidence for a direct interaction between IgG and thymic DP T, CD4 T, and CD8 T cells is presented. The small RNA-seq analysis identified ten mature miRNAs that were modulated by AD IgG compared to mock condition (miR-181b-5p, hsa-miR-130b-3p, hsa-miR-26a-5p, hsa-miR-4497, has-miR-146a, hsa-let-7i-5p, hsa-miR-342-3p, has-miR-148a-3p, has-miR-92a and has-miR-4492). The prediction of the targetome of the seven dysregulated miRNAs between AD and mock control revealed 122 putative targets, and functional and pathway enrichment analyses were performed. Our results enhance our understanding of the mechanism by which IgG can collaborate in thymic T cells in the setting of infant AD.     

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC’s interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.     

Staphylococcus aureus Exfoliative Toxin E,Oligomeric State and Flip of P186: Implications for Its Action Mechanism

Staphylococcal exfoliative toxins (ETs) are glutamyl endopeptidases that specifically cleave the Glu381-Gly382 bond in the ectodomains of desmoglein 1 (Dsg1) via complex action mechanisms. To date, four ETs have been identified in different Staphylococcus aureus strains and ETE is the most recently characterized. The unusual properties of ETs have been attributed to a unique structural feature, i.e., the 180° flip of the carbonyl oxygen (O) of the nonconserved residue 192/186 (ETA/ETE numbering), not conducive to the oxyanion hole formation. We report the crystal structure of ETE determined at 1.61 Å resolution, in which P186(O) adopts two conformations displaying a 180° rotation. This finding, together with free energy calculations, supports the existence of a dynamic transition between the conformations under the tested conditions. Moreover, enzymatic assays showed no significant differences in the esterolytic efficiency of ETE and ETE/P186G, a mutant predicted to possess a functional oxyanion hole, thus downplaying the influence of the flip on the activity. Finally, we observed the formation of ETE homodimers in solution and the predicted homodimeric structure revealed the participation of a characteristic nonconserved loop in the interface and the partial occlusion of the protein active site, suggesting that monomerization is required for enzymatic activity.     

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as “nitrate tolerance”, which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2.     

Conversion of Extracted Oil Cake Fibers into Bioethanol Including DDGS,Canola, Sunflower,Sesame, Soy,and Peanut for Integrated Biodiesel Processing

We have come up with a novel, integrated approach for making biodiesel by in-house producion of ethanol after fermentation of hexane extracted edible oil cake fiber. In addition, we have demonstrated how ethanol could be manufactured from commonly available oil cakes (such as canola, sunflower, sesame, soy, peanut) and dried distiller’s grains with solubles (DDGS). The edible oil cakes and DDGS were hexane extracted, ammonia fiber expansion pretreated, enzymatically hydrolysed and fermented to produce ethanol. From all the oil cakes tested in this work, DDGS and peanut oil cake showed the most promising results giving more than 180 g of glucose/kg of oil cake. These two feedstock’s were hydrolyzed at 15% solids loading and fermented by a native strain of Pichia stipitis. Most sugars were consumed during the first 24 h, with no pronounced inhibition of P. stipitis by the degradation products in the hydrolysate. Xylose consumption was more effective for peanut cake hydrolyzate compared to DDGS.     

Evaluation of the effect of probiotic cultures added to commercial yogurt over a known population of Listeria monocytogenes and Escherichia coli O157:H7

The effect of probiotic cultures over Listeria monocytogenes and Escherichia coli O157:H7 during yogurt storage was evaluated. Two different yogurt brands, one with additional probiotic cultures (Lactobacillus casei and L. acidophilus) were inoculated with known populations (106 UFC/g) of either L. monocytogenes or E. coli O157:H7 in three different times and stored for 32 days at 5 degrees C. Every four days the count of lactic bacteria, the added pathogens and pH was evaluated, according to the methodology described in the Bacteriological Analytical Manual. The pH and lactic bacteria population were constant during the testing period. Yogurt with additional probiotic cultures reduced the population of L. monocytogenes in 8 days, the population of E. coli O157:H7 in 16; yogurt with no additional probiotics took 20 days to reduce L. monocytogenes to non-detectable levels and even after 28 days of storage, E. coli O157:H7 was cultured. In this work, the beneficial effects of additional probiotic cultures in yogurt is confirmed again.     

Global supply chain planning for pharmaceuticals

The shortening of patent life periods, generic competition and public health policies, among other factors, have changed the operating context of the pharmaceutical industry. In this work we address a dynamic allocation/planning problem that optimises the global supply chain planning of a pharmaceutical company, from production stages at primary and secondary sites to product distribution to markets. The model explores different production and distribution costs and tax rates at different locations in order to maximise the company's net profit value (NPV).Large instances of the model are not solvable in realistic time scales, so two decomposition algorithms were developed. In the first method, the supply chain is decomposed into independent primary and secondary subproblems, and each of them is optimised separately. The second algorithm is a temporal decomposition, where the main problem is separated into several independent subproblems, one per each time period. These algorithms enable the solution of large instances of the problem in reasonable time with good quality results.     

Polyphosphates and pyrophosphates of hexopyranoses as allosteric effectors of human hemoglobin: synthesis, molecular recognition, and effect on oxygen release

Polyphosphorylated and perphosphorylated hexopyranose monosaccharides and disaccharides were synthesized from parent or partially protected carbohydrates as potential allosteric effectors of hemoglobin. A study toward the construction of seven- and eight-membered cyclic pyrophosphates was also performed on the sugars which had the proper orientation, protection, and number of phosphates. All final compounds were tested for their efficiency on oxygen release from human hemoglobin. Several compounds presented higher potency than myo-inositol hexakisphosphate, which is the most efficient of the known allosteric effectors of hemoglobin. Structure-activity relationships were analyzed. The affinity and efficiency depend on the number of phosphates attached to the carbohydrate skeleton and are related primarily to the number of negative charges present. Other effects operate, but play a lesser role.     

Steam reforming of methanol over a CuO/ZnO/Al2O3 catalyst part II: A carbon membrane reactor

The reaction of methanol steam reforming was studied in a carbon membrane reactor over a commercial CuO/ZnO/Al₂O₃ catalyst (Süd-Chemie, G66 MR). Carbon molecular sieve membranes supplied by Carbon Membranes Ltd. were tested at 150 °C and 200 °C. The carbon membrane reactor was operated at atmospheric pressure and with vacuum at the permeate side, at 200 °C. High methanol conversion and hydrogen recovery were obtained with low carbon monoxide permeate concentrations. A sweep gas configuration was simulated with a one-dimensional model. The experimental mixed-gas permeance values at 200 °C were used in a mathematical model that showed a good agreement with the experimental data. The advantages of using water as sweep gas were investigated in what concerns methanol conversion and hydrogen recovery. The concentration of carbon monoxide at the permeate side was under 20 ppm in all simulation runs. These results indicate that the permeate stream can be used to feed a polymer electrolyte membrane fuel cell.