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Nojoomi S.,University of California at Davis | Koehl P.,Shields Avenue
BMC Bioinformatics | Year: 2017

Background: The amino acid sequence of a protein is the blueprint from which its structure and ultimately function can be derived. Therefore, sequence comparison methods remain essential for the determination of similarity between proteins. Traditional approaches for comparing two protein sequences begin with strings of letters (amino acids) that represent the sequences, before generating textual alignments between these strings and providing scores for each alignment. When the similitude between the two protein sequences to be compared is low however, the quality of the corresponding sequence alignment is usually poor, leading to poor performance for the recognition of similarity. Results: In this study, we develop an alignment free alternative to these methods that is based on the concept of string kernels. Starting from recently proposed kernels on the discrete space of protein sequences (Shen et al, Found. Comput. Math., 2013,14:951-984), we introduce our own version, SeqKernel. Its implementation depends on two parameters, a coefficient that tunes the substitution matrix and the maximum length of k-mers that it includes. We provide an exhaustive analysis of the impacts of these two parameters on the performance of SeqKernel for fold recognition. We show that with the right choice of parameters, use of the SeqKernel similarity measure improves fold recognition compared to the use of traditional alignment-based methods. We illustrate the application of SeqKernel to inferring phylogeny on RNA polymerases and show that it performs as well as methods based on multiple sequence alignments. Conclusion: We have presented and characterized a new alignment free method based on a mathematical kernel for scoring the similarity of protein sequences. We discuss possible improvements of this method, as well as an extension of its applications to other modeling methods that rely on sequence comparison. © 2017 The Author(s).


Nojoomi S.,University of California at Davis | Koehl P.,Shields Avenue
BMC Bioinformatics | Year: 2017

Background: Alignment-free methods for comparing protein sequences have proved to be viable alternatives to approaches that first rely on an alignment of the sequences to be compared. Much work however need to be done before those methods provide reliable fold recognition for proteins whose sequences share little similarity. We have recently proposed an alignment-free method based on the concept of string kernels, SeqKernel (Nojoomi and Koehl, BMC Bioinformatics, 2017, 18:137). In this previous study, we have shown that while Seqkernel performs better than standard alignment-based methods, its applications are potentially limited, because of biases due mostly to sequence length effects. Methods: In this study, we propose improvements to SeqKernel that follows two directions. First, we developed a weighted version of the kernel, WSeqKernel. Second, we expand the concept of string kernels into a novel framework for deriving information on amino acids from protein sequences. Results: Using a dataset that only contains remote homologs, we have shown that WSeqKernel performs remarkably well in fold recognition experiments. We have shown that with the appropriate weighting scheme, we can remove the length effects on the kernel values. WSeqKernel, just like any alignment-based sequence comparison method, depends on a substitution matrix. We have shown that this matrix can be optimized so that sequence similarity scores correlate well with structure similarity scores. Starting from no information on amino acid similarity, we have shown that we can derive a scoring matrix that echoes the physico-chemical properties of amino acids. Conclusion: We have made progress in characterizing and parametrizing string kernels as alignment-based methods for comparing protein sequences, and we have shown that they provide a framework for extracting sequence information from structure. © 2017 The Author(s).


The nutritional demands of the immune system may result in tradeoffs with competing processes such as growth and reproduction. The magnitude of the nutritional costs of immunity is largely unknown. Thus, we examine the lysine content of the systemic components of the immune system in adult male chickens (Gallus gallus domesticus) in a healthy condition (maintenance) and following a robust Escherichia coli-specific immune response. Lysine was used as a metric, because it is found both in leukocytes and in protective proteins. The dynamics of subsets of leukocytes were monitored in primary and secondary immune tissues (thymus, bone marrow, and spleen) that would be expected to be involved in the response following iv injection of E. coli. The systemic immune system at maintenance has the same lysine content as 332 average-sized feathers, 16% of an egg, or 5.4% of a pectoralis muscle from an adult chicken. During the acute-phase response to E. coli, the additional lysine needed would equal 355 feathers, 17% of an egg, or 5.5% of a pectoralis muscle. The acute-phase proteins accounted for the greatest proportion of lysine in the immune system at maintenance and the proportion increased substantially during an acute-phase response. Hypertrophy of the liver required more lysine than all of the leukocytes and protective proteins that were produced during the acute-phase response. Size of the liver and levels of protein during the acute phase returned to normal during the time when the adaptive response began to utilize significant quantities of lysine. The catabolism would release a surfeit of lysine to provision the anabolic processes of the adaptive response, thus making proliferation of lymphocytes and production of immunoglobulins very cheap. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.


The immune response is thought to be costly and deters from growth and reproduction, but the magnitude and sources of these costs are unknown. Thus, we quantified the changes in mass of leukocytes (CD4+ and CD8+ T cells, Bu1+ IgM+ and Bu1+ IgG+ B cells, monocytes/macrophages, heterophils and thrombocytes) and protective plasma proteins in systemic (non-mucosal) components of adult chickens injected intravenously with dead Escherichia coli. During the first day after E. coli injection most types of blood leukocytes decreased and α-1-acid glycoprotein increased. Specific IgM, specific IgY, total IgM, Bu1+ lymphocytes in the spleen and bone marrow and thymic CD8+ lymphocytes increased at 5d post-injection. Quantitatively, the increases in the weight of cells and antibodies due to E. coli were dwarfed by the increase in the weight of the liver and acute phase proteins. Thus the acute phase response was markedly more costly than the subsequent adaptive response. The weight of the cells and proteins of the systemic immune system prior to challenge was 0.14% of body weight. Following E. coli injection, the additional weight of the immune components and the hypertrophy of the liver resulted in a 3.6-fold increase in weight which is equivalent to 18.5% of a large egg. © 2013 Elsevier Ltd.


The immune response is thought to be costly and deters from growth and reproduction, but the magnitude and sources of these costs are unknown. Thus, we quantified the changes in mass of leukocytes (CD4(+) and CD8(+) T cells, Bu1(+) IgM(+) and Bu1(+) IgG(+) B cells, monocytes/macrophages, heterophils and thrombocytes) and protective plasma proteins in systemic (non-mucosal) components of adult chickens injected intravenously with dead Escherichia coli. During the first day after E. coli injection most types of blood leukocytes decreased and -1-acid glycoprotein increased. Specific IgM, specific IgY, total IgM, Bu1(+) lymphocytes in the spleen and bone marrow and thymic CD8(+) lymphocytes increased at 5d post-injection. Quantitatively, the increases in the weight of cells and antibodies due to E. coli were dwarfed by the increase in the weight of the liver and acute phase proteins. Thus the acute phase response was markedly more costly than the subsequent adaptive response. The weight of the cells and proteins of the systemic immune system prior to challenge was 0.14% of body weight. Following E. coli injection, the additional weight of the immune components and the hypertrophy of the liver resulted in a 3.6-fold increase in weight which is equivalent to 18.5% of a large egg.


The nutritional demands of the immune system may result in tradeoffs with competing processes such as growth and reproduction. The magnitude of the nutritional costs of immunity is largely unknown. Thus, we examine the lysine content of the systemic components of the immune system in adult male chickens (Gallus gallus domesticus) in a healthy condition (maintenance) and following a robust Escherichia coli-specific immune response. Lysine was used as a metric, because it is found both in leukocytes and in protective proteins. The dynamics of subsets of leukocytes were monitored in primary and secondary immune tissues (thymus, bone marrow, and spleen) that would be expected to be involved in the response following iv injection of E. coli. The systemic immune system at maintenance has the same lysine content as 332 average-sized feathers, 16% of an egg, or 5.4% of a pectoralis muscle from an adult chicken. During the acute-phase response to E. coli, the additional lysine needed would equal 355 feathers, 17% of an egg, or 5.5% of a pectoralis muscle. The acute-phase proteins accounted for the greatest proportion of lysine in the immune system at maintenance and the proportion increased substantially during an acute-phase response. Hypertrophy of the liver required more lysine than all of the leukocytes and protective proteins that were produced during the acute-phase response. Size of the liver and levels of protein during the acute phase returned to normal during the time when the adaptive response began to utilize significant quantities of lysine. The catabolism would release a surfeit of lysine to provision the anabolic processes of the adaptive response, thus making proliferation of lymphocytes and production of immunoglobulins very cheap.

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