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Previously, a consortium of Pharma and not-for-profit organisations described a consensus machine learning approach to predict blood stage malaria inhibition [14]. The approach taken involved, first, each partner training a model following the same protocol based on their own in-house data. The models were then shared within the consortium without revealing the confidential information contained in the underlying chemical entities. Proprietary datasets were further obscured by only sharing descriptor weights for the subset of descriptors important in the individual models. A consensus approach, combining several models, showed improved predictivity performance compared to the individual models. The method was subsequently evaluated by selecting and then screening a set of compounds, resulting in a 3-fold enrichment. However, for a number of practical reasons, including the dependence on commercial software, the project was terminated at this stage, and critically, a prediction platform freely available for wider use was not delivered.

Urea and sodium have similar dialyzer transfer characteristics as both are small solutes, are non-protein bound, and have comparable effective blood water flow. Subsequently, the principles of urea clearance can be applied to Na+ dialysance.

Ionic dialysance can be measured periodically in real time during HD without blood sampling by OCM software embedded in dialysis machines. By this technique, the dialysate conductivity at the dialyzer inlet is briefly altered from baseline, which leads to a change of the dialysate conductivity at the outlet. Ionic dialysance is then calculated using conductivity values at the inlet and outlet at two different points [10]. The value of Dcn.t/V is then determined using the mean of conductivity dialysance (\(D_{{{\text{cn}}}}\)), session length (t), and TBW (V) and is displayed on the dialysis machine screen.

Lp-PLA2 is an enzyme that mainly exists in combination with lipoprotein particles in blood circulation, with 80-85% bound to LDL, approximately 15-20% bound to HDL [19]. Da Silva et al. analyzed the influence of obesity on Lp-PLA2 and found that enzyme activity was positively associated with BMI and the function of Lp-PLA2 changes with adolescent obesity [20]. A positive correlation also had been established between Lp-PLA2 levels and Tch, LDL-c and apoB, and a negative correlation with HDL-c and apoA I, which was confirmed by the results of this study. These data suggest that Lp-PLA2 is present in atherogenic lipoproteins. Similarly, the confirmation of a positive correlation with ALT, GGT and TBIL can be associated with the secretion of Lp-PLA2 from liver cells [21], which may be the principal source of biliary Lp-PLA2 responsible for the adjustment of gastrointestinal PAF and phospholipid metabolism [22]. Stafforini et al. found that apoB was the factor most strongly correlated with Lp-PLA2 levels, which manifests a strong bonding force with Lp-PLA2 due to its carboxyl terminus [23]. ApoB is a structural protein of lipoproteins, excluding HDL-c, and plays an important role in transporting lipids to extrahepatic tissues and recognizing LDL receptors. Some studies indicated that Lp-PLA2 induced WBC activation and inflammatory responses in vitro, and that this activation may be associated with a rapid increase in circulatory Lp-PLA2 expression [24, 25]. Yoshida et al. found that Lp-PLA2 may play an important role in scavenging oxidized phospholipids in RBC membranes and in maintaining the normal rheological properties of erythrocytes [26]. Furthermore, Uydu et al. reported that serum Lp-PLA2 was positively associated with the variations of Hs-CRP in stable CAD patients and was a more reliable indicator of coronary stenosis [27]. These findings may help explain the positive correlations observed between Lp-PLA2 levels and Hs-CRP, HGB, WBC, and RBC in this study. Taken together, the data suggest that after Lp-PLA2 is bound to LDL via apoB, lysophosphatidylcholine and free oxidized fatty acids, two strong pro-inflammatory factors, are produced through the hydrolysis and oxidation of phospholipids, thereby promoting chronic inflammation and atherosclerosis [28].

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy.

Common γ-chain cytokines, of which IL-2, IL-15 and IL-21 are members, are important in NK cell activation, maturation, and proliferation. IL-15 has a well-recognized role in maturation, survival, and homeostatic expansion of NK cells. The discovery of IL-21 was linked to its role in proliferation and maturation of NK cells [49], but subsequent studies have been widely disparate, identifying it as both activating and suppressive [50], [51], [52]. Although soluble IL-21 alone does not induce significant proliferation of mature murine NK cells and IL-21R knockout mice have normal NK cell numbers [50], IL-21 synergizes with IL-2, IL-15, and Flt-3L in the generation of NK cells from bone marrow [49] and cord blood [49], [53], [54], [55], [56]. IL-21 may activate NK cell lytic activity through upregulation of costimulatory receptors, perforin, and granzyme [57]. To exploit this potential of these cytokines, we developed membrane-bound chimeras of IL-21 (mbIL21) and IL-15 (mbIL15), and investigated NK cell expansion, phenotype, and function in response to K562 aAPCs genetically modified with mbIL21 and/or mbIL15.

G6Pase-α (UniProt P35575) is a membrane-bound enzyme that catalyses the final step in glucose synthesis; it is therefore of critical importance to maintaining blood sugar levels. To our knowledge, no experimental structure exists, but previous studies have attempted to characterize the transmembrane topology44 and active site45. Our prediction has very high confidence (median pLDDT of 95.5) and gives a nine-helix topology with the putative active site accessible via an entry tunnel that is roughly in line with the surface of the endoplasmic reticulum (Fig. 3a and Supplementary Video 1). Positively charged residues in our prediction (median pLDDT of 96.6) align closely with the previously identified active site homologue in a fungal vanadium chloroperoxidase (PDB 1IDQ; r.m.s.d. of 0.56 Å; 49 out of 51 aligned atoms)46. As these enzymes have distinct functions, we investigated our prediction for clues about substrate specificity. In the G6Pase-α binding pocket face, opposite the residues shared with the chloroperoxidase, we predict a conserved glutamate (Glu110) that is also present in our G6Pase-β prediction (Glu105) but not in the chloroperoxidase (Fig. 3a). The glutamate could stabilize the binding pocket in a closed conformation, forming salt bridges with positively charged residues there. It is also the most solvent-exposed residue of the putative active site, suggesting a possible gating function. To our knowledge, this residue has not been discussed previously and illustrates the novel mechanistic hypotheses that can be obtained from high-quality structure predictions.

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Blood Bound Epub Download Software HOT!

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