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Phylogeny of the mucosal immune system
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Robert D. Miller, Irene Salinas
Although a direct homolog of IgA has not been found in amphibians, that does not mean they lack specialized mucosal antibodies. Amphibians such as Xenopus laevis contain at least three Ig heavy-chain isotypes: IgM, IgY, and IgX (see Table 2.1). As in birds, IgY is functionally analogous to IgG in mammals. Amphibian IgX is believed to be the functional analog of the IgA found in birds, reptiles, and mammals. Like avian and mammalian IgA, frog IgX is mainly expressed at mucosal sites such as the intestine and is secreted in a polymerized form, in this case as a hexamer. However, IgX is not related to IgA and is more similar in sequence to IgM. Amphibian species such as Xenopus also express J chain and use it to form polymerized secretory IgM. They also have a pIgR that binds J chain suggesting the role of pIgR in IgX transport across epithelial surfaces. Curiously, however, Xenopus IgX is unable to interact with J chains owing to a stop codon that truncates the last constant domain. IgX therefore polymerizes in the absence of J chain. IgX responses in Xenopus larvae gut appear to be T-independent since they are not affected by thymectomy. Thymectomy also does not alter the composition of the Xenopus gut microbiome.
Replicase
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
A nrfA gene, a direct functional analog of the hfq gene, was identified in Azorhizobium caulinodans (Kaminski et al. 1994). The deduced amino acid sequence of the nrfA gene product was similar to that of the Hfq. The similar structure and function were attributed to the yrp gene of Yersinia enterocolitica (Nakao et al. 1995). The brg gene of avirulent Erwinia carotovora was shown to function as an analog of the hfq gene (Chuang et al. 1999).
Three-Dimensional Structures of the Chemokine Family
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Wayne J. Fairbrother, Nicholas J. Skelton
Tables 1 and 2 show that the MGSA solution structure most closely resembles that of the IL-8 crystal structure. At the monomer level, the orientation of the 30s-loop in the solution structure of MGSA resembles that observed in the IL-8 crystal structure more closely than the conformation observed in the IL-8 solution structure (Figure 3A and B). Interestingly, the hydrogen bonds observed between His33 and either Gln8 or Glu29, in the NMR and X-ray structures of IL-8, respectively, are not observed for the equivalent His34 in the MGSA structure. In MGSA the pKâ of His34 is ~5.8 (as opposed to a pKa of ~4.9 observed for His33 in IL-8); therefore, it is unlikely to be the acceptor of a hydrogen bond under the solution conditions used for the NMR structural study (pH 5.5).14 Substitution of His33 with alanine (and other amino acids) in IL-8 leads to a fully functional analog,34 suggesting that the functional relevance of the conformational differences observed for this histidine residue is probably minimal.
Bootstrap aggregated classification for sparse functional data
Published in Journal of Applied Statistics, 2022
In this study, we too consider the FPCA method for sparse or irregularly observed functional data, but focus on the classification problem. While the FPCA has been commonly used for the classification problem in functional data, various other methods have also been proposed. James and Hastie [7] proposed a functional linear discriminant analysis (FLDA) for sparse functional data using an expectation-maximization (EM) algorithm. James [6] and Müller and Stadtmüller [13] extended the generalized linear model to a functional analog, while Leng and Müller [11] applied a functional logistic regression based on FPC scores to temporal gene expression data and compared the results with those of the B-spline basis method. Lee [10] presented a support vector machine (SVM) based on FPC scores, and Rossi and Villa [16] proposed a functional SVM (FSVM), extending the SVM to functional data. Song et al. [19] compared the classifiers based on FPC scores using linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), k-nearest neighbor (KNN) classifier, and SVM. More recently, Fan et al. [5] proposed a kernel-induced random forest for functional data classification and applied it to temporal gene expression data.
Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors
Published in mAbs, 2021
Nicola J. Mason, Nicholas Chester, Ailian Xiong, Antonia Rotolo, Ying Wu, Sho Yoshimoto, Patrick Glassman, Gayathri Gulendran, Don L. Siegel
We have now engineered A1mut2 as an IgGB, which is the functional analog of the human IgG1 subtype that efficiently fixes complement and induces ADCC.41 Evaluation of this antibody in mice revealed linear PK and no evidence of toxicity over 48 hours. In these studies, A1mut2 was not found to accumulate preferentially in lymphoid-rich tissue of naïve mice (housed in a sterile environment), possibly due to the lack of CTLA4 expressed on the surface of conventional resting T cells. However, additional PK studies will need to be performed in dogs before A1mut2 can be tested in clinical trials. Our SPR analysis showed that A1mut2 has a higher binding affinity than both ipilimumab and tremelimumab (anti-human CTLA4 IgG2), which is associated with the comparatively slow dissociation rate of A1mut2 from CTLA4 (1.8 x 10 −4M−1s−1 compared to ipilimumab at 6.96 x 10−3M−1s−1).40 As such, we anticipate that the enhanced binding of A1mut2 will influence its PK properties, which might be reflected as a lower plasma AUC but improved duration of receptor occupancy, and thereby prolonged pharmacodynamic effects. This is a hypothesis that needs to be tested via direct comparison of variants with different binding affinities. It remains to be determined whether this would be associated with greater autoimmune adverse events, but it might enable clinical effects to be seen at a lower administered dose and increased inter-dosing interval.
Phosphodiesterase 5 (PDE5) restricts intracellular cGMP accumulation during enterotoxigenic Escherichia coli infection
Published in Gut Microbes, 2020
Jennifer Foulke-Abel, Huimin Yu, Laxmi Sunuwar, Ruxian Lin, James M. Fleckenstein, James B. Kaper, Mark Donowitz
The mechanism of ST is characterized by intracellular accumulation of cGMP and activation of cGMP-dependent protein kinase 2 (cGKII) to explain the disruption of intestinal fluid and ion homeostasis.11 However, the anti-constipation therapeutic linaclotide, a functional analog of ST, has been additionally described to decrease nociception via exported cGMP in rodent models and has demonstrated clinical efficacy in alleviating visceral pain in irritable bowel syndrome with constipation (IBS-C).12,13 This suggests that the effects of ST are similarly more complex than currently appreciated, and likely include activities linked to extracellular cGMP. In the case of both ST and linaclotide, the intracellular and extracellular cGMP pools have not been dissected to deduce their relative magnitudes, nor have their respective contributions to altered intestinal signaling been analyzed. The potential for effluxed cGMP to impact immune response has also not been evaluated. Preventive and therapeutic strategies will be better informed by a more complete understanding of how ST affects normal human intestinal epithelia.