Molecular defects in rheumatoid arthritis and methotrexate targets. UC = unchanged, UE = under expressed, OE = over expressed.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"597",leadTitle:null,fullTitle:"Crop Production Technologies",title:"Crop Production Technologies",subtitle:null,reviewType:"peer-reviewed",abstract:"Crop production depends on the successful implementation of the soil, water, and nutrient management technologies. Food production by the year 2020 needs to be increased by 50 percent more than the present levels to satisfy the needs of around 8 billion people. Much of the increase would have to come from intensification of agricultural production. Importance of wise usage of water, nutrient management, and tillage in the agricultural sector for sustaining agricultural growth and slowing down environmental degradation calls for urgent attention of researchers, planners, and policy makers. Crop models enable researchers to promptly speculate on the long-term consequences of changes in agricultural practices. In addition, cropping systems, under different conditions, are making it possible to identify the adaptations required to respond to changes. This book adopts an interdisciplinary approach and contributes to this new vision. Leading authors analyze topics related to crop production technologies. The efforts have been made to keep the language as simple as possible, keeping in mind the readers of different language origins. The emphasis has been on general descriptions and principles of each topic, technical details, original research work, and modeling aspects. However, the comprehensive journal references in each area should enable the reader to pursue further studies of special interest. The subject has been presented through fifteen chapters to clearly specify different topics for convenience of the readers.",isbn:null,printIsbn:"978-953-307-787-1",pdfIsbn:"978-953-51-5177-7",doi:"10.5772/1109",price:119,priceEur:129,priceUsd:155,slug:"crop-production-technologies",numberOfPages:290,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7f87c31dfd7e38f3e10cf7ec02df2201",bookSignature:"Peeyush Sharma and Vikas Abrol",publishedDate:"January 5th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/597.jpg",numberOfDownloads:60797,numberOfWosCitations:63,numberOfCrossrefCitations:20,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:87,numberOfDimensionsCitationsByBook:7,hasAltmetrics:0,numberOfTotalCitations:170,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 22nd 2011",dateEndSecondStepPublish:"March 22nd 2011",dateEndThirdStepPublish:"July 27th 2011",dateEndFourthStepPublish:"August 26th 2011",dateEndFifthStepPublish:"December 24th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"73200",title:"Dr.",name:"Peeyush",middleName:null,surname:"Sharma",slug:"peeyush-sharma",fullName:"Peeyush Sharma",profilePictureURL:"https://mts.intechopen.com/storage/users/73200/images/system/73200.jpg",biography:"Dr. Peeyush Sharma (born 24th Aug 1975) is a soil scientist who started her career as Assistant Professor in Dryland Research Sub-Station, Sher-e-Kashmir University of Agricultural Sciences and Technology-Jammu in 2004. She received MSc and PhD (Soil Science) degrees from illustrious G.B. Pant University of Agriculture & Technology, Pantnagar, Uttaranchal.\nAwards\n • Awarded Postdoctoral fellowship in prestigious Institute of Soil Water and Environmental Sciences, ARO, Volcani Centre, Israel working on FTIR techniques to ‘characterize the soil organicmatter with the application of different doses of compost in different cropping system’ for one year from (Nov 2013- Nov. 2014)\nExternally funded projects: 02\n • On farm training and demonstration of biochar for carbon sequestration and climate change mitigation in Kandi belt of Jammu: Principal Investigator: NABARD \n • Soil erosion risk mitigation and carbon sequestration potential of climate resilient agriculture practices in foothill Shivaliks –National Innovation in Climate Resilient Agriculture : Co-Principal Investigator\nTechnologies developed: Developed ‘Tilth Index Model’, Tillage, Biochar\nEXTENSION \n • Delivered lectures as Resource person in training programs for farmers and officials\n • Promotion and dissemination of low cost biochar production technology Research Publications (In Journals)\n • European Journal of Soil Science\n • European Journal of Agronomy\n • Soil & tillage research\n • Geoderma\nResearch Skills \n ▪ Tillage and mulching\n ▪ Fourier Transform Infrared Spectroscopy\n ▪ Writing and editing research manuscripts \nReviewer of Research Journals\n • Soil & Tillage Research\n • International Journal of Bio-resource and Stress Management\nBOOKS Published \n ◦ Crop Production Technology. 2011. Peeyush Sharma and Vikas Abrol. \n ◦ Resource Management for Sustainable Agriculture. 2012. Vikas Abrol and Peeyush Sharma. \nFUTURE THURST AREAS\n • Tillage\n • Biochar",institutionString:"Sher-e-Kashmir University of Agricultural Sciences and Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"136230",title:"Dr.",name:"Vikas",middleName:null,surname:"Abrol",slug:"vikas-abrol",fullName:"Vikas Abrol",profilePictureURL:"https://mts.intechopen.com/storage/users/136230/images/system/136230.jpg",biography:"Dr. Vikas Abrol (b. Nov 14, 1974), a Soil Scientist, received his PhD degree from Sher-e-Kashmir University of Agricultural Sciences and Technology - Jammu and holds PG Diploma in Ag. Marketing, PG Diploma in Business Management, PG Diploma in Rural Development and Diploma in Computer Application as additional qualification.\nAwards\n • Awarded Postdoctoral research fellowship for one year by Ministry of Agriculture, State of Israel to pursue research “Biochar: Mechanism of action as soil and water conservation agent in agricultural soils” in Volcani Centre, Agricultural Research Organization, Israel. \n • Awarded research fellowship for one academic year in Volcani Centre, Agricultural Research Organization, Israel to pursue research on “Efficacy of synthetic polymers (Anionic PAM) on soil and water conservation”.\n • Best Paper Award 2015, for Best Paper in National Seminar organized by Society for Community Mobilization, IARI, New Delhi \n • Best Research Paper 2015, in Indian Journal of Soil Conservation, in Soil Science and Agronomy\nExternally funded projects: 03\n\nHe started his professional career as Assistant Professor/Jr. Scientist at Dryland Research Substation, Dhiansar and published research accomplishments in the journals of international reputation like the European Journal of Agronomy, European Journal of Soil Science, Journal of Soil and Sediments, Journal of the Science of Food and Agriculture, Agricultural Mechanization in Asia, Africa and Latin America etc., with high impact factor and edited two international books, “Crop Production Technologies” and “Resource Management for Sustainable Agriculture”. He served as reviewer of research articles in international journals like Soil Science Society of America Journal, Agronomy for Sustainable Development, Land Research and Development, Indian Journal of Agricultural Sciences, Indian Journal of Dryland Agricultural Research and Development, Indian Journal of Soil Conservation, Journal of Experimental Biology and Agricultural Sciences and International Journal of Agriculture Sciences etc. His research interests entail using biochar for offsetting climate change by soil carbon aggradation, runoff quality and soil erosion control, soil quality evaluation, soil and water pollution. He holds specialization in using biochar and synthetic polymers (PAM) for erosion control, infiltration improvement and soil structural stabilization. He also served in Krishi Vigyan Kendra (extension services) and conducted trainings to farmers and officials of line departments. He is serving as Resource person for Prasar Bharti, Department of Agriculture, SAMETI, ATMA, National Fertilizer Limited, Indian Potash Association. He has presented papers in national and international conferences and seminars. He is life member of the Indian Journal of Soil Conservation, Indian Journal of Dryland Agriculture and Research, International Biochar Initiative, Friends of Israel Biochar Researchers Network, Biochar India e-group and his future endeavours envisage focuses on research to address two vital natural resources - soil & water and carbon aggradation in resource poor soils of dryland areas.",institutionString:"Sher-e-Kashmir University of Agricultural Sciences and Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu",institutionURL:null,country:{name:"India"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"311",title:"Plant Genetics",slug:"agronomy-plant-genetics"}],chapters:[{id:"25577",title:"Crop Models as Decision Support Systems in Crop Production",doi:"10.5772/28976",slug:"crop-models-as-decision-support-systems-in-crop-production",totalDownloads:4628,totalCrossrefCites:1,totalDimensionsCites:6,hasAltmetrics:0,abstract:null,signatures:"Simone Graeff, Johanna Link, Jochen Binder and Wilhelm Claupein",downloadPdfUrl:"/chapter/pdf-download/25577",previewPdfUrl:"/chapter/pdf-preview/25577",authors:[{id:"76066",title:"Prof.",name:"Simone",surname:"Graeff",slug:"simone-graeff",fullName:"Simone Graeff"},{id:"77710",title:"Prof.",name:"Wilhelm",surname:"Claupein",slug:"wilhelm-claupein",fullName:"Wilhelm Claupein"},{id:"111048",title:"Dr.",name:"Johanna",surname:"Link",slug:"johanna-link",fullName:"Johanna Link"},{id:"120291",title:"Dr.",name:"Jochen",surname:"Binder",slug:"jochen-binder",fullName:"Jochen Binder"}],corrections:null},{id:"25578",title:"Crop Water Requirements in Cameroon’s Savanna Zones Under Climate Change Scenarios and Adaptation Needs",doi:"10.5772/27803",slug:"crop-water-requirements-in-cameroon-s-savanna-zones-under-climate-change-scenarios-and-adaptation-ne",totalDownloads:2756,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Genesis T. 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The traditional paradigm for autoimmunity dates back over a century to the German bacteriologist, and early pioneer of immunology, Paul Ehrlich, who postulated that if the immune system encounters an autoantigen, damaging outcomes ensue. He described the autoimmune phenomenon as “horror autotoxicus” or the horror of self-toxicity. Today, this basic idea persists even in the ‘modern era’ utilizing biochemical and molecular-based approaches to immunology. We are taught that recognition of self as foreign by the adaptive immune system is the basis for autoimmunity. Thus, the identity of the autoantigen(s) responsible for these illnesses remains the Holy Grail for scientists committed to uncovering the origins of these diseases.
While many are focused on the identity of this antigen, we have opted for a slightly different approach to this centuries-old problem. We would argue that the identity of the autoantigen is not as important as the cell that sees this antigen. Our approach suggests a failure of the responding immune cell, particularly the T helper cell. In fact, recognition of self is essential for T cell survival and immune homeostasis. The immune system must recognize ‘self’ in order to protect the host.[1, 2] In lieu of traditional approaches that may involve animal models, our work has focused on the patients and their immune cells to investigate the molecular underpinnings of disease. We have also observed that common therapies to treat autoimmune disease, particularly, rheumatoid arthritis (RA), while efficacious, have ill-defined mechanisms elucidating their function. Therefore, a large portion of our investigation of rheumatoid arthritis examines methotrexate (MTX) responses using
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
c-Fos | \n\t\t\tUC | \n\t\t\t+ | \n\t\t\tIncreases apoptosis sensitivity | \n\t\t
c-Jun ( | \n\t\t\tUC | \n\t\t\t+ | \n\t\t\tIncreases apoptosis sensitivity | \n\t\t
\n\t\t\t\t DNA-PKcs ( | \n\t\t\tUE UE | \n\t\t\t- + | \n\t\t\t- Increases lincRNA-p21 transcripts | \n\t\t
JNK2 ( | \n\t\t\tUE | \n\t\t\t+ | \n\t\t\tIncreases apoptosis sensitivity and p53 protein expression | \n\t\t
lincRNA-p21 p21 ( | \n\t\t\tUE UE | \n\t\t\t+ + | \n\t\t\tReduces NF-κB activity Activates cell cycle checkpoints | \n\t\t
p53 ( | \n\t\t\tUE | \n\t\t\t+ | \n\t\t\tActivates cell cycle checkpoints and reduces NF-κB activity | \n\t\t
NF-κB activity RanGAP1 ( | \n\t\t\tOE UE | \n\t\t\t+ - | \n\t\t\tReduces active NF-κB - | \n\t\t
Molecular defects in rheumatoid arthritis and methotrexate targets. UC = unchanged, UE = under expressed, OE = over expressed.
Rheumatoid arthritis is a chronic, inflammatory condition of the small and large joints characterized by inflammation of the synovium, or lining of the joint.[3] While the precise etiology of this disease remains unknown, the growing appreciation for the molecular basis of this disease has provided several clues. Particular emphasis has been placed on the cell types found in the joint spaces of patients with active disease.[4, 5] Lymphocytes are the most common cell infiltrate found in the synovial space. In fact, of these lymphocytes, the majority are T lymphocytes making up approximately 30-50% of all infiltrating cell types in the synovium.[6] Of the T lymphocytes found in the RA synovium, it has been reported that the majority are CD4+CD45RO+ memory cells.[7] B cells constitute about 5% of the sublining synovial cells.[7] Clonal expansion of the B cells in the joint spaces of RA subjects suggests a maturation process driven by an antigen, which still remains unidentified. In normal tissue, the synovial space is only 1 or 2 cells in depth and is comprised of both Type A (macrophage-like) and Type B (fibroblast-like) cells.[7] However, in active RA this number increases ten-fold and is primarily thought to be the consequence of hypercellularlity due to the increase of both Type A and Type B cells.[7, 8] Many studies have suggested that Type A cells in RA display an activated phenotype and via circulation are constantly replenished from the bone marrow. Locally, while in the joint spaces, these Type A, macrophage-like cells produce “pro-inflammatory cytokines, chemokines, and growth factors” that in turn activate fibroblast-like synoviocytes and induce these cells to produce additional pro-inflammatory mediators including “IL-6, prostanoids, and matrix metalloproteinases.” [7, 9, 10] This process can create both paracrine and autocrine signaling networks that give rise to the chronic synovitis and recruitment of additional immune cells to the joint, which eventually erodes the extracellular matrix and destroys the joint space. This phenomenon is referred to as the ‘pannus’, an expansive synovial tissue.[7] Phenotypically, this pannus closely resembles a tumor. Nuclear factor κB (NF-κB), a transcription factor that is ubiquitously expressed and functions as a critical regulator of cell proliferation, differentiation, and inflammation, is also overexpressed in the RA synovium. Briefly, nuclear factor κB consists of five proteins, c-Rel, RelA (p65), RelB, p50/p105, and p52/p100 that form either a homodimer or heterodimer.[7, 9] c-Rel, RelA, and RelB function as the major transactivation subunits. Unless activated, these subunits reside in the cytoplasm along with their inhibitor, IκB.[7] Phosphorylation of IκB causes IκB to be degraded by the proteasome, thus releasing NF-κB dimers to migrate to the nucleus where they localize to promoter regions of target genes.[7] Electromobility shift assays show constitutively high levels of p50 and p65 proteins in the synovium of rheumatoid arthritis subjects and induction of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α through IKK signaling pathways.[9] Depletion of p65 or the IKK family member, IKKβ, in the synovial tissue with siRNAs or introduction of dominant negative mutants reduces levels of these pro-inflammatory cytokines.[11]
In addition to increased levels of NF-κB, both synoviocytes and T cells in RA exhibit defects in expression and function of the guardian protein p53 leading to inability of these cells to undergo apoptosis and to resulting loss of genomic integrity.[8, 12] p53 is a critical regulator of cell cycle progression and reduced p53 levels or inactivating p53 mutations have also been found in a number of cancers including leukemia. Linking the contribution of these observations to the pervasive, non-resolving inflammation found in RA is a common goal in the management of the disease. Without this understanding, most therapeutics lack the specificity to precisely target the underlying defects contributing to disease progression. As such, most newly developed biologic agents attempt to disrupt the downstream, NF-κB activation-pro-inflammatory cytokine loop, by using drugs like etanercept, which selectively blocks the inflammatory cytokine, TNF-α.[13] These newer biologic therapies have added to the ability of physicians to improve outcomes and decrease disability. However, despite these advances excess mortality observed in patients with RA continues and recent data suggest that the mortality gap between RA patients and the rest of the population continues to widen.[14, 15] How, then, can we design therapies to target these observed defects? In the mid-twentieth century, we witnessed the birth of molecular medicine and the era of intelligent drug design. While most of the drugs developed during this period sought to treat cancer, very few of these early medications remain first in class therapies today and have since been replaced by more targeted therapies. Yet, one drug, MTX, first developed more than a half century ago, remains the standard of care for the treatment of RA.
Folates are critical components of cellular division, and DNA and RNA synthesis. The synthetic form of folate, folic acid, was first isolated in the early 1940s and was found to exacerbate acute forms of leukemia when added to a patient’s diet.[16-18] Conversely, additional studies found that decreasing dietary amounts of folic acid decreased the leukemia cell counts in patients. From these early observations, work began to design analogues of folic acid, which could be used to treat cancer, particularly leukemia. Aminopterin was designed to reduce proliferation of cancerous cells via the inhibition of folate. Seminal work by Sidney Farber, a pathologist at Harvard Medical School and Boston Children’s hospital, demonstrated that aminopterin produced remission in children diagnosed with acute lymphoblastic leukemia (ALL).[18-20] Even though this only produced brief remissions, it was proof of concept that folate antagonism could suppress the proliferation of malignant cells. Thus, the clinical efficacy of aminopterin in the treatment of ALL cemented aminopterin as one of the world’s first chemotherapeutics.[18]
Work that followed nearly a decade later by Sidney Futterman, Michael Osborn, and Frank Heunnekens identified dihydrofolate reductase (DHFR) from chicken liver as the enzyme responsible for the reduction of folic acid to metabolically active forms.[18, 21] Thus, blockade of DHFR was implicated as a therapeutic target of chemotherapeutic doses of aminopterin. Isolation of this enzyme allowed for the creation of more potent inhibitors of DHFR. Specifically, another folate analog, MTX, was identified in a study of leukemia-bearing mice and when compared to aminopterin increased survival in these mice.[18] From these initial data in mice, two reports found that MTX at very high doses cured women diagnosed with choriocarcinoma, a malignant trophoblastic cancer of the placenta.[19] This was the first solid tumor to be cured by a drug in humans and stimulated interest in investigating the effects of MTX in additional forms of cancer.[18, 22] Of particular interest was the reduced side effect profile observed in the MTX-treated cohort. Compared to radiation or alkylating agents that can lead to infertility or additional malignancies, MTX monotherapy did not produce these deleterious effects.[18] Today, MTX is currently used in the treatment of large cell or high grade lymphomas, head and neck cancer, breast cancer, bladder cancer, and osteogenic sarcoma.[18] It is often used in combination with other therapies including 6-mercaptopurine (6MP). Studies have shown that the combination of MTX, 6MP, vincristine, and prednisone improve patient outcomes in the treatment of ALL.[18] In particular, a treatment regiment first prescribing MTX and following with 6MP in sequence improves cure rates.[18]
Given the immunosuppressive potential of aminopterin and MTX in the treatment of malignancy, Gubner et al reported in 1951 that proliferative responses of formalin injection in rat paws was abrogated with aminopterin treatment.[18, 23] Further, in a small population of patients with active rheumatoid arthritis, Gubner and colleagues showed that the overwhelming majority of patients treated with aminopterin developed reduced indices of disease activity. When the therapy was stopped, the patients experienced relapse. The toxicities reported included nausea and diarrhea, even at low doses (1-2 mg/day).[18] Due to these discomforts, MTX, which closely resembles aminopterin, was substituted.[18] Patients were able to tolerate MTX reasonably well at low doses. The role of aminopterin, and later MTX, was also investigated in other non-neoplastic diseases including psoriasis, a chronic skin condition producing thick patches of irritated skin that manifest as red or white scales and similar therapeutic benefits were observed.[18] It is interesting to note that this early report describing the therapeutic potential of MTX or other folate analogs was largely ignored for a quarter century. It would not be until the late 1980s that MTX is approved for the treatment of rheumatoid arthritis.[24]
Given the therapeutic potential for MTX in the treatment of these forms of cancer and even autoimmune disease, significant resources have been expended to investigate its mechanism of action. Bertino et al provided significant insight demonstrating that MTX is actively transported into cells through reduced folate transporter 1 (RFT-1).[25] MTX, like naturally occurring folates, is polyglutamated once taken up by the cell. Folates exist in cells as polyglutamates through the addition of 6 glutamyl groups in a gamma peptide linkage to the folate substrate using the enzyme folylpolyglutamate synthase (FPGS).[26] These long-lived MTX polyglutamates remain in the liver of patients for a long period as well as in the bone marrow myeloid precursors.[26] Polyglutamation of MTX occurs within 12-24 hours after treatment and polyglutamates constitute the active form of the drug.[26, 27] Thus, MTX is commonly referred to as a pro-drug, a compound that undergoes a biochemical modification to become its active form. Inhibition of DHFR, at pharmacologically relevant doses of MTX required for the treatment of malignancy, inhibits purine, pyrimidine, and thymidylate biosynthesis through reduced levels of tetrahydrofolate (FH4) in the cell. Blockade of these enzymes, which are critical for nucleotide generation, halts rapid division of tumor cells through induction of apoptosis. Thus, one goal of MTX therapy is to increase the cellular cytotoxicity profile. Alterations to this pathway in the form of mutated RFT-1 or DHFR can lead to MTX resistance in cancer patients.[19, 26] Interestingly, cancer subjects resistant to MTX often exhibit increased levels of DHFR protein. It is hypothesized that gene amplification events may take place that are long-lived in tumor cells or that amplification occurs through extrachromosomal elements, called amplisomes, that contain DHFR genes.[26] This is currently an area of active exploration and future studies are required to determine the exact mechanisms.
While MTX is still used in the modern treatment of cancer, it is in the treatment of rheumatoid arthritis that physicians have observed MTX’s greatest, long-term effectiveness. Often heralded as the drug that revolutionized the field of rheumatology, low-dose, once-weekly MTX differs by approximately three orders of magnitude (milligrams versus grams) compared to dosing schemes required for the treatment of malignancies. When the FDA first approved MTX in 1988 for the treatment of rheumatoid arthritis, it was assumed that the mechanism of action by which MTX exerts its anti-inflammatory effects in rheumatoid arthritis would closely resemble the mechanism of action found in the treatment of cancer. However, despite considerable experience with MTX in the treatment of RA, we are still uncovering clues as to the exact mechanism or mechanisms MTX employs to produce its anti-inflammatory effects.
Given the pro-inflammatory, anti-apoptotic phenotype exhibited by both synoviocytes and T cells in RA, and the ability of MTX to mitigate indices of inflammation it is logical to question if MTX may exert its anti-inflammatory properties through modulation of these pathways. For the past 30 years, the precise mechanisms employed by MTX to exert its anti-inflammatory effects in RA have been the focus of thorough investigation.[18, 25, 28-41] In the treatment of cancer, MTX induces apoptosis by blocking the folate-dependent processes involved with DNA and RNA synthesis ultimately leading to cell death. Curiously, however, folic or folinic acid supplementation in RA patients receiving MTX does not reverse its anti-inflammatory effects in randomized, blinded trials.[16, 18, 40, 42] Thus, other mechanisms have been proposed. A prevailing theory is that MTX exerts its mechanism of action through a number of different mechanisms including release of adenosine that function in parallel to blockade of nucleotide synthesis.[16] Reduced levels of methyl donors including tetrahydrofolate (FH4) and methyltetrahydrofolate through inhibition of DHFR blocks generation of lymphotoxic polyamines through methionine and S-adenosylmethionine (SAM).[17, 27, 36, 40, 42, 43] Polyamine reduction has been posited as one anti-inflammatory mechanism since polyamines can be converted to lymphotoxins.[42] However, use of 3-deazaadensoine, a transmethylation inhibitor, does not demonstrate a significant clinical benefit in RA patients.[42] Yet, low-doses of MTX also inhibit chemotaxis in monocytes through a process reversed by S-adenosylmethionine supporting the contribution of this pathway in RA.[44] The retention of MTX polyglutamates in cells exceeds its half-life in plasma, suggesting that the MTX metabolites persist in tissues. These polyglutamates have also been shown to inhibit aminoimidazolecarboxamidoribonucleotide (AICAR) transformylase resulting in elevated intracellular AICAR levels. RA subjects exhibit high levels of AICAR in their urine during the course of MTX therapy.[16, 42] Increased AICAR levels are strong inhibitors of adenosine monophosphate (AMP) and adenosine deaminases, involved in the consumption of AMP and adenosine to IMP and inosine. Accumulation of adenosine in tissues has anti-inflammatory effects and AICARriboside, which also inhibits adenosine deaminase, is increased in RA.[42, 45] MTX has also been shown to enhance vasodilation leading to increased blood flow through inhibition of adenosine deamination in whole blood in humans.[46] The direct quantification of MTX-mediated adenosine release in humans receiving MTX has been unsuccessful largely because the half life of adenosine in blood and tissue is very brief making these measurements technically challenging.[42, 47] In animal models, however, the anti-inflammatory effects of MTX are mediated by adenosine using the carrageenan-induced air pouch model of inflammation and reversals with A2A adenosine receptor antagonists and supplementation of adenosine deaminase.[42, 48] Thus, one mechanism by which MTX achieves its anti-inflammatory effects is by stimulating increased synthesis and release of adenosine, which in turn, activates adenosine receptors to block various pro-inflammatory paths.
Other studies have also shown that MTX inhibits T cell activation, induces apoptosis, and alters expression of T cell cytokines and adhesion molecules.[28, 32, 49, 50] Additional work by Phillips et al posit that the anti-inflammatory properties of MTX are critically dependent upon the ability to produce reactive oxygen species in both T cells and monocytes, which ultimately lead to apoptosis.[31] Given the pronounced anti-inflammatory properties of low-dose MTX therapy in RA, it is unclear how the known biochemical pathways affected by MTX, e.g. inhibition of DHFR, activation of adenosine synthesis and release, should produce this anti-inflammatory profile. Our work has sought to explore the question of whether either additional biochemical pathways are targeted by MTX or additional biochemical consequences of DHFR inhibition by MTX may produce these anti-inflammatory properties observed in subjects with RA receiving low-dose MTX as therapy.
While initially developed as a chemotherapeutic, MTX (MTX) has been the mainstay for RA treatment for nearly four decades. Once-weekly administration of 7.5 to 25 milligrams yields optimal clinical outcomes, compared to the 5000 mg/week dosage used in the treatment of malignancy.[16, 18] RA patients treated with MTX experience reduced pain, and improved joint score and function typically within three months of initiation of treatment. The tight control and suppression of inflammation in early stages of disease has been advocated as the basis of documented disease modifying effects. Yet, the mechanisms accounting for the anti-inflammatory effects of MTX remain incompletely understood. Questions also remain as to the specific targets necessary to develop new therapeutics beyond MTX for the treatment of RA.
Our initial studies in RA examined differences in expression patterns of genes in healthy control subjects and patients diagnosed with autoimmune disease. The goal of these experiments was to identify a subset of genes that could distinguish between healthy individuals and patients with autoimmune disease.[51-53] Our expectation was that we would identify genes that encode proteins typically involved in pro-inflammatory processes. Instead, we found that patients with RA significantly underexpressed a panel of genes that are typically considered prototypical ‘cancer genes’ in peripheral blood mononuclear cells that encode proteins required for cell cycle arrest, maintenance of genomic integrity, and induction of apoptosis. Many cancers have inactivating mutations in these genes. Specifically, these studies established that defects in expression of
Since mechanisms by which low-dose MTX achieve therapeutic benefit in RA are incompletely understood and how the above deficiencies in cell cycle regulation and apoptosis may contribute to RA pathogenesis, we chose to initiate studies to compare RA subjects on MTX to RA subjects not receiving MTX therapy. Initially, we found that RA subjects receiving MTX therapy exhibited increased expression of genes encoding Fos and Jun that form the AP-1 transcription factor. In addition, expression of a number of genes induced by the AP-1 transcription factor is elevated in RA subjects receiving MTX therapy. Further, we were also able to reproduce these findings in tissue culture models via dose-dependent induction of
One signaling pathway that activates the AP-1 transcription factor is via activation of Jun-N-terminal kinase (JNK), a MAP kinase, which phosphorylates Jun resulting in increased transcriptional activity of AP-1. MTX also activates JNK in our tissue culture models and MTX-dependent activation of JNK is responsible for the observed increases in
Since our
We further probed the mechanism by which MTX increases sensitivity of cells to apoptosis by asking if MTX restores the cell cycle checkpoint deficiencies we described previously. Since MTX increases activity of JNK in our tissue culture models, we asked if levels of JNK are decreased in subjects with RA not receiving MTX. We found highly significant deficiencies of
Our studies outlined above clearly establish that MTX is a strong transcriptional activator, both in tissue culture models as well as in RA patients as part of their therapy. This is achieved in large part via activation of JNK. One of the best-studied proteins induced by MTX is p53, which itself is a strong transcriptional activator and the gene expression program induced by p53 allows p53 to carry out many of its cellular functions such as cell cycle arrest and induction of apoptosis. Further, transcript levels of genes encoding p53 and its transcriptional targets are largely depressed in RA patients. However, whether losses of these gene transcripts and corresponding proteins can contribute to the pro-inflammatory state characteristic of RA or how they might contribute to this pro-inflammatory state is less clear.
The NF-κB transcription factor is probably one of the best-characterized pro-inflammatory transcription factors. Many genes that encode pro-inflammatory cytokines, chemokines, and lymphocyte adhesion molecules possess NF-κB binding sites in their promoters and require activation of NF-κB for their increased expression in response to extracellular inflammatory stimuli. For these reasons, our next series of experiments analyzed the influence of MTX upon transcriptional activity of NF-κB, a central regulator of the inflammatory response, in two cells types: T cells and primary fibroblast-like synoviocytes (FLS) from RA subjects. We also examined NF-κB activity in the PBMC of RA patients receiving and not receiving MTX. In T lymphocytes, we found that MTX is a strong inhibitor of activation of NF-κB in response to various extracellular stimuli. In T cell tissue culture models, MTX inhibits activation of NF-κB via BH4 depletion and JNK activation. Further, the inhibition of NF-κB activity in T cells by MTX is dependent upon MTX-mediated induction of p53. In patients with RA, NF-κB activity is chronically elevated in T helper cells and this elevation is reversed by MTX therapy. Taken together, we believe these studies provide a direct link between elevated activity of the pro-inflammatory, pro-cell survival transcription factor, NF-κB in RA and depressed levels of the pro-apoptotic, pro-cell cycle control transcription factor, p53, and show how induction of p53 by MTX results in subsequent loss of NF-κB activity in RA T helper cells.
Synovial fibroblast-like cells also activate NF-κB in response to extracellular stimuli and elevated levels of NF-κB activity have been demonstrated in RA synovial tissues. Therefore, we asked if MTX also inhibits activation of NF-κB in response to extracellular stimuli and if this inhibition is achieved via BH4 depletion and JNK activation. Low concentrations of MTX effectively inhibit NF-κB activation in synovial fibroblasts in tissue culture. However, MTX does not act by depleting BH4 and activating JNK as it does in T cells. In fact, genes characteristically induced by MTX in T cells, e.g.
Schematic illustrating alternate pathways of MTX-mediated inhibition of NF-κB activity in T cells and synoviocytes.
We have explored the connection between NF-κB and p53 further, as these transcription factors are two central regulators of the adaptive immune response. NF-κB modulates the response to exogenous stimuli, whereas p53 modulates intrinsic stress responses through initiation of “cell cycle arrest, apoptosis, or senescence, eliminating clones of cells with DNA damage and its resulting mutations”.[63] In general terms, NF-κB and p53 are functionally antagonistic. NF-κB is considered a pro-survival, pro-inflammatory transcription factor while p53 is an anti-survival, anti-inflammatory transcription factor. The precise mechanisms explaining the connection between p53 and NF-κB in the context of immune cells remains largely unexplored and is likely to be stimulus-, cell-, and/or disease-specific. The basic understanding in a healthy cell is that DNA damage, hypoxia, or oncogene activation elicit p53 responses that activate cell cycle arrest, senescence or apoptosis, targeting genes that are pro-apoptotic such as
Examination of the PBMC and synovium of RA subjects demonstrates that NF-κB is significantly overexpressed. Also present are reduced levels of p53. p53 drives induction of genes that both prevent DNA damage and repair damaged DNA. Together with NF-κB, these master regulators of internal and external stimuli must achieve a careful balance. Each transcription factor responds to a different form of cellular stress, adopting two very different strategies that have evolved into mutually exclusive processes under normal physiologic conditions.[63] It has also recently become appreciated that the metabolic fates of RA T cells are reprogrammed. RA T cells are energy deficient as evidenced by reduced glucose consumption, lactate production, and intracellular stores of ATP.[71, 72] Yang et al identified defects in 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a critical regulator of glycolysis, as the mediator of the observed defects as constitutive overexpression of PFKFB3 repaired the glycolytic insufficiency. Most interestingly, the study also demonstrated that deficiencies of PFKFB3 reduce ROS levels in cells. Our studies with methotrexate suggest that increased ROS generation is a therapeutic benefit of MTX therapy as apoptotic death of proliferating T cells is essential for T cell homeostasis. Thus, the contribution of metabolic ‘rewiring’ and the therapeutic potential of targeting these biomarkers represent attractive targets for clinical intervention.
To induce cell cycle arrest or apoptosis, the transcriptional program activated by p53 is mediated, in part, by induction of the long non-coding RNAs (lncRNAs), lincRNA-p21 and PANDA.[73, 74] lncRNAs are relatively newly discovered species of RNA. lncRNAs are transcribed from genes that look like protein-coding genes. Approximately 10,000 lncRNA genes have been discovered in the human genome so they may be as abundant as protein-coding genes.[75] These genes contain exons and introns and lncRNAs are spliced to mature lncRNAs just like mRNAs. The difference between lncRNAs and mRNAs is that lncRNAs are littered with translational stop codons throughout their sequence and thus cannot be translated into proteins and therefore exist as RNA species. As a class, lncRNAs have multiple functions. Major functions are the stimulation or inhibition of transcription of protein-coding genes. These target protein-coding genes are oftentimes, but not always, located in close proximity in the genome to the gene encoding the effector lncRNA. These lncRNAs generally act by recruiting the epigenetic machinery to target gene loci to establish activating or repressive histone marks. lncRNAs also interfere with translation of proteins. Additional mechanisms of action of lncRNAs are to regulate function, stability and activity of proteins. Thus, lncRNAs exhibit a broad spectrum of activities that play key roles in many cellular processes.[76-80] Further, individual lncRNAs can have multiple modes of action. An example is lincRNA-p21. One function of lncRNA-p21 is to repress transcription of certain genes in response to p53 activation.[73] A second function is to modulate translation of certain mRNAs.[81] A third function is to modulate the stability of the transcription factor HIF-1α, thus regulating its activity.[82] A fourth function is to stimulate transcription of
Because both transcript and protein levels of p53 and p21 are depressed in RA and are MTX target genes, we were interested to learn if the lncRNAs, lincRNA-p21 or PANDA, are differentially regulated in RA and/or may be MTX target genes. We have found that lincRNA-p21 transcript levels are depressed in RA T cells and lincRNA-p21 is a MTX target gene in T cells.[84] However, TP53 and lincRNA-p21 levels do not correlate with each other in T cells from subjects with RA or healthy controls suggesting that levels of p53 do not determine levels of lincRNA-p21 in T cells as they do in other cell types. Further, although lincRNA-p21 is strongly induced by MTX in T cells in our tissue culture models and lincRNA-p21 levels are restored to normal in RA patients receiving MTX therapy, induction of lincRNA-p21 does not appear to be dependent upon p53 activation under these conditions in these cell types. In T cells, induction of lincRNA-p21 by MTX is also not mediated by BH4 depletion, nitric oxide synthase ‘uncoupling’ and JNK activation or by adenosine release and adenosine receptor activation.[84]
Increased DNA damage is also observed in RA T cells. The two major sentinels of DNA damage responses are the enzymes ATM and DNA-PKcs and these enzymes are also deficient in RA T cells.[57] Thus, these enzyme deficiencies may explain the accumulation of DNA damage observed in RA T cells. In T cells, stimulation with low concentrations of MTX results in activation of DNA-PKcs (phosphorylation) but not activation of ATM. Induction of lincRNA-p21 by MTX requires DNA-PKcs activation. In RA T cells, MTX therapy also restores
We also asked if activation of DNA-PKcs and induction of lincRNA-p21 by MTX contributes to MTX-dependent activation of NF-κB in response to extracellular stimuli, such as TNF-α. This is clearly the case. Inhibition of DNA-PKcs, but not ATM, reverses MTX-dependent inhibition of TNF-α mediated NF-κB activation. Further, use of siRNAs to deplete either p53 mRNA or lincRNA-p21 reverses the ability of MTX to inhibit TNF-α mediated NF-κB activation. Thus, we conclude from these studies that multiple pathways are activated in T cells by methotrexate to achieve its anti-inflammatory effects. A graphic summary of the pathways we have discovered as a result of these studies is summarized in Figure 2.
Summary of previously known and new mechanisms of methotrexate action
It has also been shown that telomeres of CD4+ cells are shortened in subjects with rheumatoid arthritis. On average, the telomeres of lymphocytes and even progenitor cells, such as CD34+ hematopoietic stem cells, are 1.5kb shorter compared to control resulting in accelerated immune system aging. [85, 86] Given that the immune system divides on average once a year and the average telomeric base pair (bp) loss is approximately 50bp, the immune system of RA subjects is approximately 25-30 years older than that of an unaffected individual. This phenotype is present in early disease and in untreated patients. So a question to ask is how are these traits conferred? Genetic studies have informed our knowledge of this disease by revealing the association of human leukocyte antigen (HLA) serotypes with autoimmune disease susceptibility. In the case of rheumatoid arthritis, susceptibility is associated with the HLA-DR4 allele. The relative risk for RA is four times greater in carriers compared to unaffected individuals with current female to male ratios suggesting an approximate 3:1 distribution.[87-89] Specifically, HLA-DRB1*04 remains the most important genetic risk factor for rheumatoid arthritis. If you examine healthy donors, and track the telomeric length of HLA-DRB1*04 +/- individuals as they age, donors with a positive HLA-DRB1*04 haplotypes exhibit premature aging in their CD4+ T cells with average telomeric length approximately 1.0-1.5kb shorter than HLA-DRB1*04 negative individuals.[64-66] It was further observed that this phenomenon of early immune aging was also found in the neutrophils of HLA-DRB1*04 positive individuals with concomitant accumulation of pre-senescent CD4+ T cells in healthy HLA-DRB1*04+ individuals measured by accumulation of CD28 null T cells in the total CD4+ lymphocyte population.[90-92]
In general, telomere loss is a measure of what is termed cellular senescence. Cellular senescence can arise by a number of mechanisms that include DNA damage, deficiencies of DNA damage response and repair pathways, as well as elevated NF-κB activity. It has also been argued that cellular senescence is a pathogenic mechanism in RA. Further, in experimental models, loss of p21, p27 or p53 can produce cellular senescence as well as pro-inflammatory or autoimmune phenotypes. Similarly, increased NF-κB activation can produce pro-inflammatory or autoimmune phenotypes. These same defects are seen in RA. Thus, one can imagine a continuous pathogenic loop of deficiencies in proteins involved in DNA damage responses and cell cycle control and increased NF-κB activity culminating in RA pathogenesis (Figure 3). MTX-dependent restoration of these deficiencies in DNA damage response and cell cycle control proteins that culminate in inhibition of chronic NF-κB activation reinforces this point. What is unclear is if there are dominant ‘drivers’ in this pathway or will any of the aforementioned defects that arise produce this pathogenic loop? This model raises the question of whether these defects arise via genetic or environmental mechanisms and understanding this question may improve our understandings of the origins of this disease. There may be other methods to interfere with this pathogenic loop. If developed, these methodologies may aid in the treatment of RA.
One hundred years ago, the only drug in the physician armamentarium to manage RA was aspirin.[93] Soon after, gold salts were commonly prescribed from approximately 1930-1980. Penicillamine, anti-malarial drugs, and sulfasalazine were subsequently introduced from in the 1970s and 1980s.[24] However, despite introduction of these pharmacologics, the disease course of most RA patients progressed and was not adequately controlled. It wasn’t until the introduction of disease-modifying anti-rheumatic drugs, such as MTX, that physicians saw significant improvement in long-term outcomes, especially when MTX was combined with other therapies. When we initiated our studies to examine the anti-inflammatory properties of MTX, we thought that there would be a single biomarker we could target to achieve the same outcome with less toxicity, as subjects taking MTX have reported hair loss, nausea, and fatigue. However, as we examine the molecular basis for this drug in RA, we find that not only does it stimulate the adenosine pathway, which results in reduced NF-κB activation in FLS, but it also activates the BH4 pathway and induces lincRNA-p21 in T cells. Both of these pathways lower NF-κB transcriptional activity and function
Hypothetical mechanistic loop that connects known molecular defects in RA to pathogenesis.
Targeted therapies that have been approved over the past decade have resulted in many first-in-class drugs. However, the majority of these first in class drugs were the result of phenotypic assay screening, and not through targeted approaches.[94] Interestingly, most targeted approaches result in follow-on drugs that are prescribed in combination with other ‘anchor’ therapies in human disease. An interesting area of future investigation would be to design small molecules that selectively target BH2 reduction to BH4 and alternatively induce lincRNA-p21 expression. Given the diverse effects we see both
In our model, DNA damage accumulates every day in individuals as a result of environmental exposures, UV or ionizing radiation, oxidative stress, chemical exposures, cell replication, inflammatory stress in response to infection, normal metabolic activities produce oxidants, or smoking.[97-104] Smoking is well established as a significant environmental risk factor for RA. Normally, activation of cell cycle checkpoints and the DNA damage response machinery repair DNA damage. However, in RA, via intrinsic mechanisms regulated by the presence of HLA-DRB1*04 alleles or other pathways, these repair mechanisms, DNA-PKcs, ATM, and cell cycle checkpoints, JNK2, p53, p21, p27, CHEK2, RANGAP1 are defective, resulting in failure to repair DNA and loss of genomic integrity.[53, 105-108] Failure to repair DNA and/or cell cycle checkpoint defects results in chronic NF-κB activation and induction of pro-inflammatory cytokines, producing a continuous cycle of events causing chronic inflammation, which underlies the pathogenesis of RA. Future studies are planned to examine the contribution of these defects to the pathogenesis of RA.
Gene symbol-Protein names
Functions: senses DNA damage and initiates DNA repair pathways and pathways to induce cell cycle arrest or apoptosis, also involved in telomere maintenance
Functions: senses DNA damage and initiates similar pathways as Atm, also involved in non-homologous recombination, necessary for successful formation of T and B cell receptors
Functions: activated by Atm in response to DNA damage, phosphorylates and activates p53
Functions: transcription factor, participates in an array of stress responses inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism.
Functions: Inhibits activity of cyclin-CDK2 or –CDK4 complexes to inhibit cell cycle progression at G1, p53 target gene
Functions: Inhibits activity of cyclin E-CDK2 or cyclin D-CDK4 complexes to inhibit cell cycle progression at G1, p53 target gene
Functions: Phosphorylates a number of transcription factors including c-Jun to activate the AP-1 transcription factor and regulate stress responses and apoptosis, also pro-inflammatory as many genes that encode cytokines and chemokines have AP-1 binding sites in their promoter
Functions: along with Fos, forms the AP-1 transcription factor
Functions: along with Jun, forms the AP-1 transcription factor
Functions: GTPase activator for the nuclear Ras-related protein, Ran, and converts it from the active state to the GDP-bound inactive state
Functions: transcription factor involved in many cellular processes commonly categorized as a pro-survival, pro-inflammatory transcription factor
Telomeresregions of repetitive DNA sequences at the ends of each chromosome, telomere ends shorten after each cell division, cellular senescence occurs when the telomeres become too short and this inhibits further cell division
Supported by grants from the National Institutes of Health (R21 AR063846, R01 AI044924, R42 AI53948), the National Center for Advancing Translation Sciences (UL1TR000445), the American College of Rheumatology Within Our Reach grant program (ACR124405) and the National Science Foundation Graduate Research Fellowship Program (DGE0909667).
Recycling is the process of converting materials from all kinds of waste to produce new products. Textile recycling implies the reuse and reprocessing of clothing scraps or any fibrous textile material [1]. All types of consumer or industry discarded textile goods are used as textile wastes for recovery. It is obvious that recycling, which has evolved into sustainability over time and its importance has been understood even in ancient times. It can be applied in many fields of the textiles as textile-to-textile (closed-loop) recycling or textile-to-nontextile (open-loop) recycling [2].
The demand for textiles and clothing is increasing day by day as a result of the increasing population, rising living standards, and the fast changing fashion trends [3, 4, 5]. Consequently, the amount of textile waste increases, and there are accumulations in landfills [4]. In addition to the consumption of high amounts of textile products, the packaging of these products also causes an increase in waste piles [6].
Textile and clothing waste causes environmental problems and deterioration of ecological balance. Therefore, the reclaim and disposal of waste clothing and textiles are important issues. Unfittingly and uncontrolled disposal of waste cause major problems [5]. The importance of recycling is considered in three subjects by Ref. 7 as economic, social, and environmental subjects [7]. Recycling of textile waste and diversifying the content of recycled raw materials could be a way to support the country’s economy. The employment opportunities in the textile sector as in other sectors increase with well-run waste management. The recycling sector is an important supplier to many industries, and wastes are considered as cheap raw materials [8]. A wide variety of garment brand companies offer their products that contain recycled materials at certain rates, as a social responsibility issue in the market and to increase their prestige. It also adds profit to the company by paying less for recycled materials obtained from waste products.
Although there are several methods for the disposal of clothing waste, the most effective methods are recycling and reuse. Evaluation of waste clothing is very complex since clothes are made from different raw materials and may contain various accessories. Clothing may have many components such as labels, sewing threads, buttons, zippers, and interlining, and these components make the separation process difficult. Clothing recycling and textile recycling are two independent topics that are needed to be considered separately [5]. Textile wastes arise out of many production processes, such as fiber and filament manufacture, spinning, weaving, knitting, nonwoven, and clothing manufacturing [9]. In this context, textile wastes can be classified as pre-consumer and post-consumer wastes [10, 11]. Pre-consumer textile waste includes manufacturing waste from the processing of fibers, yarn, fabric, and nonwovens and clothing manufacturing [12]. Pre-consumer textile waste is generally seen as “clean waste” as it is released during the textile production process [13, 14].
When all these wastes are well managed, positive results emerge both in terms of providing economic gains via the recycling of materials and reducing the ecological damage to the world. Despite all advantages, there are recycling limits for all kinds of textile wastes. Not only for textile wastes but also for other solid wastes recyclability variates. Some types of wastes can be easily and well recycled, whereas some types cannot or can formidably be recycled [1]. These limits pave the way for the emergence of new recyclable fibers for the textile industry.
The purpose of this chapter is to present a systematic study for recycling of textiles mentioning the limits and alternative sustainable fibers. The content started with the history of recycling, continued with processes, standards, and certificates about textile recycling. Subsections of recyclable common textile fibers and new recyclable textile fibers are given in detail.
Recycling dates back to ancient times [15]. It is claimed that waste management and waste disposal processes date to BC in several references [16, 17]. Recycling is known as an efficient and effective solid waste management system [18]. In 4000 BC, silkworm wastes were used as protein source food in fish raising in China [19]. Scientifically, the foundations of recycling were laid in the 1980s [20].
When we consider textile recycling, it is known that it is as old as recycling in other fields. There are even references stating that it is one of the oldest fields, so textile recycling is called original recycling [21]. China hosted applications where recycled fibers from used clothing were obtained by hand carding and mixed with virgin fibers BC [14]. The textile recycling industry took its first steps in the thirteenth century [22]. In pre-modern societies, there were sustainability models based on the reuse and recycling of textiles [14]. For example, recycling has been done for years in India, both at the household and industrial level [23]. In the early and mid-1800s, reclaimed spin waste and rags were used for the manufacture of new products, and the invention of carbonization made it a unique technique to separate textile waste comprising of cellulose-based and wool fibers blend [22].
Environmental awareness concept had been newly introduced in the 1960s. The conscious interest of consumers and producers had just begun to turn to recycle at that time. Today, it is argued that this interest has evolved into sustainability [24].
Early academic studies conducted in the 1990s focused on presenting a model for the textile waste lifecycle [25]; detailing biological, physical, and chemical treatments of textile wastes [26]; determination of the number of sewn product manufacturers that support recycling in an American state [27]; the recyclability of post-consumer fibers, and market applications, while revealing the advantages of recycling [28]. After this decade, a positive acceleration was observed in the studies on both recycling and textile recycling. When “textile” and “recycling” terms are searched in a topic currently 1843 documents in WOS were encountered at all times. Moreover, 188,487 documents were encountered with the only term “recycling” at all times. The variation of the number of publications by years are given in Figure 1 and in the first quarter of 2022, 41 documents were published about the textile recycling topic. As can be seen from the graph, the number of research on textile recycling has increased in parallel with the number of research on recycling over the years.
The number of publications encountered with search terms “recycling” and “recycling and textiles” in WOS.
Recycled fibers are used to make a variety of products. By producing yarns from recycled fibers, knitted or woven fabrics can be produced, or non-woven surfaces are obtained directly from these fibers. Recycled pre-consumer textile wastes are utilized in the construction, automotive, furniture, paper, and clothing industries. However, fibers obtained from pre-consumer textiles are used especially in coarse yarn production [29]. Many researchers studied about using pre-consumer waste and its conversion into a valuable product in the literature. Jamshaid et al. [30] span open-end rotor yarns from fibers in different blends reclaimed from yarn and fabric wastes. They evaluated the impact of various textile wastes on fiber and yarn quality. They underlined that the length and uniformity values of the fibers recycled from yarn wastes are better than those of the fibers recycled from fabric wastes. However, in terms of yarn manufacturing costs, it has been stated that yarns produced from recycled fabric/rag wastes are more economical than yarns produced from yarn wastes. The impact of cotton waste and various spinning conditions on rotor yarn quality was investigated by Halimi et al. [31]. The results showed that the quality of the rotor yarn is not affected by the addition of 25% waste in the first passage of the draw frame. Yilmaz et al. [32] produced yarns by blending the fiber wastes taken from the blow room, the carding and sucked in the draw frame, roving, and conventional ring spinning machines with the virgin cotton fibers at 5 different amounts varying from 5% to 40%. They emphasized that by designing machinery and process steps based on waste fiber type, it can be possible to produce yarns that are in comparable quality values and low cost.
The post-consumer textile wastes consist of clothing and home textiles that consumers no longer need for various reasons, such as damage, pulling on, or going out of fashion [14]. Contrary to pre-consumer wastes, post-consumer wastes are known as dirty and household waste [33]. Post-consumer wastes are evaluated with reuse and recycling techniques or incineration. The options to be applied to post-consumer waste vary according to many criteria such as the wear condition of the clothing, fiber content, and the technology of the recycling facilities [34]. The progress in recycling technology supports the sustainable disposal of waste clothing, and recycling is far more environmentally friendly and socially beneficial than incineration. In addition to this, technological advancements are required to produce upcycle products from waste clothing. Improvements in the collection and disposal of post-consumer textiles can be made with the application of environmental protection policies [5].
Post-consumer waste of sufficient quality is utilized as second-hand clothing by other consumers or sold to third-world countries. The volume of consumer waste is quite high, and clothes that cannot be worn again are shredded into fibers and used in new products, similar to pre-consumer wastes [6, 14]. The process of producing new clothing from post-consumer waste includes collecting waste, obtaining fiber from waste, and producing yarn by using a certain amount of blend in the yarn production stage [34].
When compared to original fibers, recycled fibers have different properties. The processes that the fibers are exposed to during the recycling process damage them and shorten their length. Fiber length is important factor in converting recycled fibers into yarn or producing nonwovens from these fibers, and the fibers must be long enough. Due to the short length of recycled fibers and the presence of non-fiber remnants such as fabric and yarn fragments, defining some quality parameters of these fibers is difficult. Fiber length, material break down degree, and fiber length distribution are three of the most widely analyzed properties of recycled fibers [35].
There are four different approaches to recycling (Figure 2) [36, 37]:
Primary approach,
Secondary approach,
Tertiary approach, and
Quaternary approach
Various recycling approaches.
Primary recycling is the most beneficial method, and in this approach, the product is recycled to its original form. This approach is also known as “original recycling.” It is aimed at synthetic fibers such as PET (polyethylene terephthalate) and PA (polyamide) [37]. In this method, which can also be blended with the similar original raw material in order to increase the product quality, cleaned and pure scraps from waste are collected and recycled. In addition to the important advantages of this process such as being cheap and easy, it also has the disadvantage that the type of recyclable material is limited [38].
Secondary recycling is the process of converting waste into a product with different physical or chemical properties than the original [39]. Secondary recycling, which converts post-consumer wastes into raw materials, includes the collection and recycling process [40]. The content of textile waste, the degree of purity of the end product, availability, cost, and processing techniques are important factors for secondary recycling.
In tertiary recycling, known as feedstock recycling, wastes are separated into chemicals through pyrolysis, gasification, hydrolysis, and condensation [41]. Tertiary recycling, which is preferred for converting plastic wastes into chemicals, monomers, or fuels, utilizes clean and well-sorted pre-and post-consumer wastes [40].
Quaternary recycling is the use of heat produced by the incineration of fibrous solid wastes [42]. In summary, primary and secondary recycling usually involve the mechanical processes of industrial by-products and waste, while tertiary and quaternary recycling includes the pyrolysis and incineration of textile wastes for energy generation [41].
Mechanical recycling is a low-cost and easy method [11], which is the preferred method for recycling a diverse variety of textile waste [43]. The recycling of post-consumer textile waste is generally carried out by mechanical recycling [42]. In the mechanical recycling technique, the fabric is broken down into fibers by cutting, shredding, carding, and other mechanical processes [44, 45]. Mechanical recycling machines gradually break the fabric into small pieces and make it fibrous, and these obtained fibers are reused in the production of yarn or nonwovens. In the mechanical recycling process, initially, wastes are sorted. Foreign components, such as metals and labels, are eliminated. After the fabric is cut into small pieces with rotary blades, it is separated into fibers by tearing [40].
Since garments are usually made from different raw materials, it is better to use pre-consumer waste instead of post-consumer waste in mechanical recycling. Fibers obtained by mechanical recycling from pre-consumer wastes such as denim scraps can be used to make higher-quality yarns. The length of the fibers recycled by the mechanical recycling process is short, despite the use of clean pre-consumer wastes [40]. The fiber length is shortened by the shredding/tearing process. The main reason for this is the friction between the fibers. Friction causes wear of fibers and melting of synthetic fibers. Lubricants are used to reduce friction between fibers during shredding and thus longer fiber lengths can be obtained [46]. In addition to the lubrication process, product quality is increased by blending original fibers with recycled fibers [45].
Recycled fiber properties such as length, fineness, and strength indicate the field the fibers can be evaluated in [47]. Good quality recycled fibers can be spun into fabrics, while lower quality fibers are used as decoration materials, construction materials [48], automotive components, insulation materials, and nonwovens [45, 47].
In thermal recycling, synthetic fibers are melted to be reshaped. The thermal recycling method is preferred for recycling synthetic fibers [48, 49]. Chips and pellets obtained by mechanical process from synthetic wastes are turned into fibers by melt extrusion [50].
Chemical recycling, which is another method used in the recycling of textile waste, is the depolymerization of polymers or the process of dissolving polymers [2]. Polymers are converted or broken down into their original monomeric building blocks by chemical and biological methods [51].
Monomer and polymer recycling are the two forms of chemical recycling. The polymer chain is frequently degraded during polymer recycling. As a result, the quality of the recycled fiber decreases. In monomer recycling, original quality fibers are obtained. While monomer recycling is only used for synthetic fibers, chemical recycling is applicable to many textile fibers [49]. In addition to the chemical recycling of synthetic fibers, such as polyesters, polyamides, and polyolefins, in cotton and polyester blend products, the fibers can be chemically separated and then converted into new fibers [47].
Downcycling occurs when the quality and economic value [40] of a product obtained from recycling processes is lower than that of the original product [2, 50]. The use of recycled clothing and home textile wastes in agriculture and gardening products, decoration materials [48], insulation materials, low-quality blankets, and upholstery fabrics are the examples of downcycling (Figure 3) [2, 50].
Downcycling applications in textile.
When the quality of the recycled material is the same or higher than the original product, this process is called upcycling [2, 50]. Upcycling is a process in which existing resources are used and converted into more useful products. This environmental-friendly process is an important step for a zero-waste policy [52]. Within the scope of sustainability and circular economy, the production of raw materials such as cotton fibers and yarns from textile wastes with polymer and monomer recycling is an example of upcycling [2, 50].
Open-loop recycling is defined as the use of a product’s raw material in a different production area. Secondary products obtained through open-loop recycling are generally destroyed after their lifetime [40]. The use of fibers obtained by recycling PET bottles in the textile industry (Figure 4) [40] and the usage of recycled textile fibers as insulation material in the construction industry are examples of open-loop recycling.
Open-loop recycling.
The reuse of recycled textile waste in the textile industry is called closed-loop recycling [2]. The use of mechanically recycled pre-consumer or post-consumer textile waste in garment production is an example of a closed-loop recycling (Figure 5) [40].
Closed-loop recycling.
The subject of recycling in textiles comes up with a lot of research based on the advantages created by the recycling process and with a limited number of studies based on recycling limits. In this subsection of the chapter, the limits of recycling in materials traditionally used in textiles are addressed.
Despite the approaches expressing that recycling is a process that only delays the conversion of waste to nature [53], several articles emphasized the importance of process development studies about the determination of recyclability limits [54]. Since it is impossible to apply a uniform recycling method for recycling all kinds of waste materials, different recycling techniques and their combinations have emerged over time [53]. For example, chemical recycling is raised in order to eliminate the limits in mechanical recycling [55]. As recycling can be classified as mechanical, chemical, thermal, and thermomechanical methods; each of them has numerous disadvantages in terms of the imperfections created on the recycled material. Considering these limits, alternatives purposed for the disposure of textile waste as anaerobic digestion, fermentation, composting, and acquisition of construction material [13].
An assessment can be made on the basis of fiber source for recycling limits. Based on the disadvantages, such as shortening or shredding the fibers created the fibers by each recycling cycle, it is stated in the literature that an average of 8 recycling cycles for synthetic fibers and an average of 5 cycles for natural fibers can be actualized [56, 57]. While the recyclability limits are more evident in natural fibers, the same rule is not valid for the fibers formed from thermoplastic polymers. This is the main reason why thermoplastic polymer-based textile waste is the most recycled waste [58].
To increase the quality of the recycled end product in cotton mechanical recycling, there is an obligation to use virgin fibers in addition to recycled fibers at a predetermined ratio. This can be attributed to the decrease in strength according to the recycling cycles as each cycle results in a lower degree of polymerization [59]. The upper usage limit of 30% for recycled cotton in fabrics is specified due to the shortened fibers. The amounts higher than this value causes decreases in fabric quality and performance [60]. Another study in the literature supported this result [61]. Since the fiber breakages are created in the mechanical recycling of cotton [59, 62], low-performance fabrics may be obtained not suitable for professional wear such as workwear, personal protective equipment, career wear, and uniforms [63].
Recycling is classified as primary and secondary recycling in several references. Secondary recycling can be handled as mechanical recycling and the limits mentioned above are also valid for this type of recycling. On the other hand, in primary recycling, the features of waste such as being from a single source and being pure are indisputable, while the low cycle number for each material and even the non-recyclability of some materials constitute these limits [64].
An important factor limiting the chemical recycling process of cotton is the use of harmful chemicals in the industry. While trying to minimize the damage to nature with waste disposal, the use of harmful chemicals which refers to the duality in this phenomenon creates greater harm to both nature and the consumer [59]. Moreover, the need for the separation of textile waste according to color and/or product type is inconvenient. One of the problems encountered in cotton recycling is that most of the cotton products are dyed ones and it is difficult to work with mixed-colored wastes [63]. Besides, there are studies proving that cotton fibers recycled from colored fabrics tended to possess lower quality values [65]. Thus, the demand for more environmentally friendly approaches continues [59].
Wool is a natural fiber that can only be mechanically recycled. The staple length of wool gets shorter with recycling, and it is used in blend ratios with virgin wool up to 70 recycled/30 virgin. The limited market of recycled wool is also a huge obstacle to the recycling of this fiber [63].
Nylon is a polymer with a wide variety of types that is stated as an infinitely recyclable polymer [66]. It is difficult to recycle nylon with mechanical recycling in the industry. In addition, the low number of nylon suppliers makes recycled nylon fibers more expensive [63]. Vidakis et al. studied the effects of multiple recycling cycles of PA12 on its properties. There was a decrease in mechanical properties above 5 recycling cycles. This weakening in mechanical properties is explained by the decrease in crystallinity and the beginning of degradation [67]. When the thermal recycling of polyamide 6 is evaluated, it was seen that a drying process is suggested before melting. It is revealed that the drying process prevents hydrolytic chain scission in wet materials and the intrinsic properties of PA6 polymer are remained [68].
Various studies were conducted in the literature in the last two decades for the determination of recycling cycle limits of polymers. PET which is a thermoplastic polymer widely used in the textile sector one of the polymers tested. Högg performed four recycling cycles on PET and characterized the basic polymer properties. He revealed that there was a considerable decrease in Young’s modulus according to the decrease in intrinsic viscosity [69].
The polyolefin fibers react with oxygen in remelting cycles. High temperature or UV light applied in remelting cycles result in molecular weight loss. The dissolution/reprecipitation process for the recycling of high-density polyethylene (HDPE) has been suggested to overcome this limit by Poulakis and Papaspyrides. It is remarked that both the polymer and the solvent has been recovered efficiently. According to this process applied as two recycling cycles to HDPE, no changes in molecular weight, distribution of grain sizes, crystallinity, and mechanical properties were observed [70]. The same researchers applied this technique to virgin PET in pellet form and PET in blow-molded bottle form in two cycles. It was observed that the properties of recycled PET did not change [71].
The effects of seven recycling cycles on PLA (polylactic acid) polymer which is also a polyester was evaluated by Pillin et al. They observed a notable decrease in the molecular weight of the polymer. They attributed the changes in stress and strain at break, modulus, and hardness via recycling cycles to the decrease in molecular weight [72]. Another group studied eight recycling cycles of PLA and concluded that there were no changes in the mechanical properties of the polymer due to the successive cycles [73].
PAN (polyacrylonitrile) is another polymer commonly used in the production of textile products as an alternative to wool. The most critical factors limiting the recycling of PAN are the easy accessibility of perfect virgin PAN and the harsh processing conditions. From this point of view, economic conditions come into play in the recycling of PAN. The high temperature applied during recycling is also shown as a disadvantage for acrylic, which is a polymer inclines to open-loop recycling [74].
Textile wastes consisting of blends of various fibers complicate the recycling process and sometimes even make it impossible. These fibers need to be separated, which should be done by expert workers to avoid problems with the recycled final product. In addition, when it is impossible to recycle these wastes, they reach their end-of-life by utilization in energy recycling [75].
From a different point of view, there are basically two main factors limiting the recycling of textile fibers. The first one is the technological limits of recycled fibers and their inability to be used within virgin fiber, yarn, or fabric production methods. The second is that the expected product quality value cannot be reached by using these recycled fibers [76].
There are two types of sustainable fashion drivers in a sustainable fashion as production and consumption drivers. Material, human and intellectual resources form the production drivers and purchasing decisions, usage, and post usage form the latter. While technical limits are considered in the first derivatives, unawareness of consumption causes a considerable increase in waste [77]. The fact that recycled materials are generally suitable for downcycling emphasizes an important point that should be evaluated economically. Another economic point is the low consumer demand for recycled products. The reason behind the low market demand is the use of dangerous chemicals in recycled products. In addition, waste sorting is a big problem and if it is not done properly, it negatively affects the recycling process from the beginning. Finally, the relevant standards are still in their infancy. All of these may be listed as examples of the limits of recycling [78].
Cotton and polyester are the most recycled fibers as referred before. Cotton is the most used type of natural fiber in the textile and clothing industry global consumption is reported as 26.16 million tons and the production rate is 26.43 million tons by the year 2021. When we evaluate cotton cultivation in terms of environmental aspects, it requires a large quantity usage of land occupation, water, and also pesticides. Due to pesticides, it pollutes clean water resources. In the textile production process, cotton dyeing needs a high amount of energy consumption, water, steam, and chemicals, such as bleaching agents, soap, softeners, and salts for obtaining the desired color [55, 79, 80]. Polyester is a non-biodegradable fiber in the environment. Its production process is very similar to polyamide. But polyester is extensively recycled especially as plastic bottles made of polyethylene terephthalate to reduce the landfills. Polyamide is used especially in carpets as referred before. But its recycling process is difficult because of the used dyes and chemicals added to its polymer solution [10].
Besides these types of common fibers, there have also been come out brands with the increasing recycling trend. Renewcell® technology is the upcoming brand from Sweden since 2017. For this process, used garments and textile production waste with high cellulosic content such as viscose, lyocell, modal, acetate, and other types of regenerated fibers (also called man-made cellulosic fibers) are used. Their accessories, such as buttons, zips are removed from the textile material, then it is turned into a slurry. Contaminants and non-cellulosic contents are sorted out from this slurry. This blend, brand named as Circulose® that is consisted of dissolved pulp from 100% recycled textiles dried and packaged as bales for being involved in the textile production process [81, 82].
Repreve® is known as the r-PET staple and filament yarns which are made from post-consumer water bottles and pre-consumer waste, and their fibers are used in many types of industrial product categories. Accessories, apparel, automotive, bedding, flooring, footwear, furnishings, medical accessories, military, outdoor, socks, and hosiery are some of them. As they stated they eliminated the processes; crude oil wellhead, crude oil refinery, Naptha, Xylenes, Paraxylene, TA (Terephthalic Acid) & MEG (Mono Ethylene Glycol). They have chip production (polymerization), extrusion, and texturing for Repreve® polyester filament yarns and feed stock preparation (polymerization), extrusion, and staple processing for Repreve® staple polyester fibers [83, 84]. Moreover, there is a recycled Nylon brand that is Repreve® Nylon 6 fibers. In production, they have also eliminated the processes; crude oil wellhead, crude oil refinery, benzene, cyclohexane, HMD (Hexamethylenediamine), adipic acid, and nylon salt. They have only chip production (polymerization), extrusion, and texturing processes [85].
Trevira® Sinfineco is the brand used for textiles that contain sustainable Trevira® products. They worked together with Thailand-based parent company Indorama whose manufactures recycled chips from PET bottles. They have certificates for recycled chips, fibers, and filaments from GRS (Global Recycled Standard) and RCS-NL (Recycled Claim Standard). Their products are mainly used in the automotive and apparel sectors. Trevira® Sinfineco PLA fibers and filaments are produced from plant sugars (sugar beet, sugar cane, and maize). So, they are recyclable and 100% biodegradable (industrially compostable) fiber materials. The plant sugar is subjected to the fermentation process and it is transformed into lactic acid. Besides their advantageous properties such as UV stability, fastness to light resistance, good wicking properties, it has less environmental impacts. 70% less CO2 is emitted and 42% less energy is consumed in the raw material production process. They have ISEGA certification for PLA fiber types used in hot water filtration applications (tea and coffee filters) and packaging materials contacting with food [86].
rPET companies supply post-consumer materials in different ways. One of these interesting materials is Bionic®, which collects its source from the coastline of the oceans and waterways to produce rPET PES. Besides environmental benefits, they also get community support both for collecting and cleaning, building up waste management systems including sorting by material and color, compacting, grinding, and warehousing. Besides, they teach the system wherever their collecting point is. Then, they send them for pelletizing. Finally, the recycling process goes in the traditional way. They have three kinds of yarns; FLX® from marine plastics, DPX® from recycled plastics, and natural or synthetic fibers for gaining softer texture, HLX® from 3 layers; core, recovered with rPET and natural fibers in the outer sheath [87].
As technological sustainability process Lenzing™ introduced Refibra™ Technology which is called as reborn Tencel® Fiber Technology and they addressed that it is one of the circular economy solutions. It is a closed-loop technology in which cotton scraps and wood are used for pulping processes. For cotton scraps, they use a special and patented method for transforming colored cotton rags into the lyocell grade pulp by dye removal process and degree of polymerization adjustment. Recycling and upgrading of cotton scraps to new virgin lyocell fibers are free from water and solvent usage. It is certified according to Recycled Claim Standard (RCS) and Global Recycle Standard (GRS) [88, 89]. Lenzing™ EcoVero™ fibers are sustainable viscose fibers that are produced by the use of certified and controlled sustainable wood sources, ecological production process, and supply chain transparency as stated. It has 50% lower emissions and water impact than generic viscose. Lenzing™ EcoVero™ fibers are certified with the EU Ecolabel. It means that the production method has a lower impact on the environment compared with other products in the market [90]. Livaeco by Birla Cellulose™ is eco-enhanced viscose manufactured using a closed-loop process. As they declared, they make a series of changes in the process to be more environmental-friendly. They used a molecular tracer so that they can follow the product from fiber stage to garment form and they can verify the product easily. They emphasize that their source is from certified sustainable forests, they consumed lower water compared with other types of natural fibers, lower greenhouse gas emissions and biodegrades in 6 weeks. They stated that cost of Livaeco™ is 4–5% higher than the conventional type of their fibers produced [91]. Livaeco™ has the FSC® C135325 certificate that refers wood is sourced from the forests following the principles of Sustainable Forestry Management provided environmental, social and economic benefits. They also have various certificates, tools, and documents about sustainability for different processes. They have Forest Stewardship Council (FSC®) certificate for obtaining wood, pulping, fiber production processes regularly; Rainforest Alliance certificate in pulping process; Higg Index, Thinkstep in fiber production step; Tracer tool (fiber, yarn, fabric, garment), OEKO-TEX 100, Sustainable Textile Solution for their Livaeco™ viscose fiber, BLOCKCHAIN for Fiber 2 Retail Process. Besides these certificates, they achieved Dark Green Shirt, Ranking in Canopy’s Hot Button Report in 2020 [92]. Kelheim Fibers have also CELLIANT Viscose which is introduced as the first in-fiber sustainable viscose infrared (IR) solution that is an alternative to synthetic fibers. They use natural minerals and embedded them into plant-based fibers. It is certified by FSC® or PEFC™ about raw material used. They are also awarded with a dark green/green shirt in Canopy’s 2021 Hot Button Report, which is a sustainability indicator for viscose fiber producers [93].
When polyamide is considered, one of the brand marks is Econyl® by Aquafil S.P.A. It has two types of nylon textile filament yarns; ECONYL® FDY yarns on beam and ECONYL® texturized yarns on cones that are both types of yarns produced via using 100% recycled post-consumer and post-industrial recycled content. They use fishnets, carpets, oligomers (generated by polymer industries), and other types of PA6 materials as wasted content. In ECONYL® plant operation processes has two steps as depolymerization step (where the specific mix of waste is transformed back into secondary raw material-caprolactam) and the purification step of caprolactam [94].
Fulgar is another company that has various types of sustainable fibers with the brand names; Q-NOVA®, Q-CYCLE®, EVO®, AMNI SOUL ECO®. Q-NOVA® PA 6.6. yarn has an eco-friendly process called as MCS (Spinning Continuous Melting). MCS is a mechanical regeneration system that does not involve using chemical materials which would lessen the sustainability of the end product. More than half of it is produced by pre-consumption waste. This waste is remolded using a mechanical regeneration process, then after, it is turned into a form of a polymer. Its prominent features are stated as lightness, breathability, having bright colors. It has certificates as The Global Recycled Standard (GRS), EU ECOLABEL, Higg index [95]. Q-CYCLE® yarn is their new eco-sustainable PA 6.6 yarn produced with their interaction with BASF’s ChemCycling™ recycling project. They use post-consumer recycled contents like plastic wastes (used tires) that is not possible to be mechanically recycled. Its certifications are under the evaluation process [96]. EVO® is the other trademark of Fulgar that is a bio-based origin polyamide that its polymerization is partially or completely sourced from castor oil (from castor seeds) [97]. AMNI SOUL ECO® has enhanced PA 6.6 formula, developed by Rhodia-Solvay group, which enables garments to be a biodegradable feature when left in landfills [98].
Considering the polyurethane known as elastane in the market, COREVA™ can be mentioned. It is a plant-based yarn obtained from natural rubber for replacing synthetic, petrol-based yarns and is patented by Candiani Denim. Organic cotton is wrapped around a natural rubber core, so they produce plastic-free yarn by replacing conventional synthetic and petrol-based elastomers. As they declared, Candiani has created an innovative, biodegradable stretch denim fabric but still, it has the features such as elasticity, physical qualities, and durability that are important factors for producing jeans [99].
Environmental issues are trending topic and their importance increase gradually. There are some international treaties to regulate the behavior of the countries to reduce greenhouse gases and protect the ozone layer. Kyoto Protocol and Montreal Protocol are exemplary treaties for the sign of industrialized countries, describing the precautions that they should take [55]. The carbon footprint is the amount of the greenhouse gases released from fossil fuels used for electricity, heating, and transportation purposes. Textile and clothing sectors are the leading sectors that have high carbon footprint generation and greenhouse gases emissions [37]. Energy is the other critical case for the textile industry. The consumed energy according to textile processes can be given as 34% for spinning, 23% for weaving, 38% for chemical process, and 5% for various purposes [100].
All the efforts for sustainability including getting certifications, discovering new sustainable processes, producing new sustainable fibers, getting textile ecolabels, United Nations’ The Sustainable Development Goals (UNSDGs) are playing a major role. United Nations’ 17 goals can be listed regularly as; no poverty, zero hunger, good health and well-being, quality education, gender equality, clean water and sanitation, affordable and clean energy, decent work and economic growth, industry, innovation and infrastructure, reduced inequalities, sustainable cities and communities, responsible consumption and production, climate action, life below water, life on land, peace, justice and strong institutions, partnerships for the goals. There are various studies about the relationship between UNSDGs and fashion brands, certifications, and new type of sustainable fibers [101, 102].
In the past, products are disposed of after the end-of-life or disuse of the products. But today, solutions and precautions for sustaining the environmental cycle are steadily taken. ISO 14040:2006 (Environmental Management-Life Cycle Assessment-Principles and Framework) is the valid standard to evaluate the sustainability of the product cycle [103, 104]. Life cycle assessment (LCA) is a methodology that is determined by the ISO 14040 and ISO 14044 [80]. It merges the environmental impacts of the studied product or service through the value chain [104]. It is possible to determine the potential environmental benefits of various systems of textile reuse and recycling processes within the methods of LCA [50]. LCA does not contain design and development stages because it is considered that design of the product has not environmental impact. But the design of the product can be affected by the other life cycle stages such as emissions to air, water, and land at each stage of manufacture, use, and disposal of the product [105].
There are various textile sustainability standards and certifications. EU Ecolabel supports Europe strategy for zero pollution and circular economy targets by minimizing products’ harmful impact on the environment. Products labeled with EU Ecolabel make a reduction in water consumption, make less pollution in the air, restrict the use of hazardous chemicals, and minimize the waste [106, 107]. Better Cotton Initiative (BCI) is claimed itself as the world’s leading sustainability initiative for cotton. Their mission is to help cotton communities survive and thrive while protecting and restoring the environment. They have selected five impact areas consisted of climate change mitigation, soil health, pesticide use, smallholder livelihoods, and women’s empowerment [108, 109]. In BCI’s Better Cotton Assurance Model, they have a roadmap for Better Cotton Farmers and farmer groups to move from baseline performance to meeting the key indicators of the Better Cotton Principles and Criteria and ultimately achieving long-term improvement goals. The model has four overarching goals. The first one is giving license to sell their cotton as Better Cotton if they can meet the standards and criteria to license for selling their cotton as Better Cotton. The second one is improvement in the framework for making sustainable practices. The third one is the development in the improvement of connection between producers and partners. The last one is measuring the sustainability performance of the farmers [109, 110].
Besides OEKO-TEX Standard 100, OEKO-TEX has series of Sustainability Standards comprising of Oeko-Tex Sustainable Textile Production (STeP), Made in Green by OEKO-TEX®, ECO PASSPORT by OEKO-TEX®, OEKO-TEX® DETOX TO ZERO. ECO PASSPORT by OEKO-TEX® is used for chemical products (textile and leather chemicals, colorants, and auxiliary agents) that are used in the textile, leather, and clothing industry. Oeko-Tex Sustainable Textile & Leather Production (STeP) is the standard for modules, such as chemical management, environmental performance, environmental management, social responsibility, quality management, health, and safety in production chain. To get Made in Green by OEKO-TEX® certificate, some criteria (some OEKO-TEX® certificates) should be taken due to finished products that consumers can buy at retailers or semi-finished products sold to companies within the supply chain. This certificate means that textile or leather products’ materials are tested for harmful substances, produced as environmentally, safe, and socially responsible workplaces are supplied [111].
GOTS is also one of the textile processing standard for organic fibers, also both for ecological and social criteria. It comprises the whole textile supply chain starting with harvesting of the raw materials till packing and labeling. It is important to use dyes and chemicals that have a low impact on environment and even it has water norms in production, besides this, it also considers fiber requirements, environmental criteria, social criteria, and traceability. GOTS have various production criteria limits. For example, additional fiber limits for natural fibers both for vegetable and animal fibers (linen, hemp, wool, silk, mohair, etc.) is up to 30%; for sustainable regenerated fibers is (Lyocell® & protein based fibers: from organic, FSC(Forest Stewardship Council™)/Programme for the Endorsement of Forest Certification (PEFC) certified recycled raw materials is up to 30%; for Recycled Claim Standard (RCS from Textile Exchange), Global Recycle Standard (GRS from Textile Exchange), Recycled Content Standard (from SCS) certified synthetic fibers (polyester, polyamide, polypropylene, and polyurethane) is up to 30%. There are also restricted fibers in blends like conventional cotton, virgin polyester, conventional angora hair, acrylic, asbestos, and carbon, silver. They have also an obligation for using virgin synthetic and regenerated fibers like viscose, modal, polyamide, elastane, and polypropylene in fiber blends as the maximum ratio is 10%. They have given some more examples like it is permitted to use 70% organic cotton, 30% lyocell from the organic plantation; but, it is not permitted to use 70% organic cotton, 30% lyocell from conventional wood [112, 113].
BlueSign® is one of the sustainability standards that offer a system with solutions for industry and brands for increasing their sustainability performance. They have various criteria such as chemical products for end-consumer use, surface treatment of metals, and plastics/non-textile substrates, fiber manufacturing, textile manufacturers, down and feathers processing, flame retardants, nanoscale materials/structures [114]. They have also a restricted substances list (RSL). In fiber manufacturing for production sites, it is stated that 99% solvent recovery (lyocell, acetate, etc.) rate should be aimed at dry spinning or wet spinning. They encourage their partners to develop fibers that meet their requirements for supporting a circular economy and to give ahead manufacturers to produce and use of recyclable and recycled fibers for circular textile production. It is obligatory for fiber manufacturing sites to pass the chemical assessment that they use Alkylphenol ethoxylates (APEO), free agents, in all preparation and sizing agents used. It is possible to give more examples for other type of fibers. In polyester fiber production, they have limited values of volatile organic compounds (VOCs) not only for year, but also limited emission factors per PET chips (one kg) and filament fiber (one kg). It is also important to have wood policy for cellulosic regenerated fibers, such as viscose, lyocell, and acetate. In production, 25% of sourced pulp fibers/pulp should be used from the wood certified by independent third-party certification with the label of the Forest Stewardship Council (FSC®). Besides this, independent third-party risk assessments, audits and on-site visits should be taken with positive results by audits (preferably a CanopyStyle Audit with at least bronze status) or independent third-party certification of sustainable forest management programs (e.g. Rainforest Alliance) [115].
The Higg Index is used as a tool for the standardization of sustainability measurement. It is comprised of five tools; the Higg Facility Environmental Module (FEM), Higg Facility Social & Labor Module (FSLM), Higg Brand & Retail Module (BRM), Higg Materials Sustainability Index (MSI), and Higg Product Module (PM). They evaluate the social and environmental performance of the value chain together with the environmental impacts of products. It gives an opportunity to consumers using the Higg Index to inform their individual sustainability strategies in crosswise topics, such as water use, carbon emissions, labor conditions, consumer goods brands, retailers, manufacturers, and governments [116].
The Recycled Claim Standard (RCS) and Global Recycled Standard (GRS) are stated as international and voluntary standards. They set requirements for third-party certification about recycled input and chain of custody. Their aim is to raise the usage ratios of recycled materials. The GRS contains also social and environmental processing requirements and chemical restrictions as additional criteria compared with RCS [117]. For RCS, labeling can be applied to all products containing at least 5% recycled material for textiles. It also enhances the traceability of recycled raw materials, transparent communication, clear labeling, and stakeholder engagement [118]. The GRS label assured that there are high percentages of recycled contents in products, the harmful impact is reduced both for people and the environment, traceability and stakeholder engagement are supplied [119].
Cradle to Cradle Certified® is another global standardization for safe, circular, and responsibly made products. It evaluates the safety, circularity, and responsibility of materials and products in five categories of sustainability performance such as material health, product circularity, clean air & climate protection, water and soil stewardship, and social fairness [120].
Forest Stewardship Council® (FSC) forest management certification endorsed that the management of forests is made by taking care of biological diversity and benefits the lives of local people and workers. There are 10 principles for forest operation for receiving FSC forest management certification. These principles include a broad range of issues, from maintaining high conservation values to community relations and workers’ rights, as well as monitoring the environmental and social impacts of forest management [121].
There are also some other sustainability standards like Cotton Made in Africa, Organic Content Standard (OCS), Soil Association Organic Standard, Responsible Down Standard (RDS), Responsible Wool Standard (RWS) [122, 123, 124, 125, 126].
Recycling has shown continuity since ancient times as a technique that people comprehended its importance towards the purpose of living with scarce resources and applied it even if not in a scientific sense. Recycling has reached scientific meaning throughout history, and then the subject has evolved towards sustainability. Textile recycling has a great place within the scope of this subject, which has been on the agenda for a long time and will also continue to be, with the advantages it creates in both environmental and economic terms. Human beings fall into textile products from the moment that they are born, they need these textile products throughout their lives (even when they die in some cultures—due to the rituals of burial with various fabrics). The indispensability of textile has always kept it at the forefront in various areas for years.
Engineering-based scientific research always aims to increase the quality of life and make the world habitable for a longer period. In this context, these purposes are embodied as the main objectives in the studies on recycling and sustainability. As the decrease in natural resources, population growth, changes in fashion causing excessive consumption of resources, and technological developments continue, the interest in recycling and sustainability will increase acceleratingly. As emphasized herein, recycling in textiles, recycling limits in textile wastes, and the search for sustainable new textile resources will continue to be hot topics of the area. In conclusion, approaches on more effective utilization of traditional fibers, the discovery, commercialization, and popularization of new sustainable fibers, and the representation of new models for the management of textile waste will be the focus of researchers for years.
The authors declare no conflict of interest.
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The chapter describes the design, implementation and integration of a ground penetrating radar (GPR) using a software defined radio (SDR) platform into the aerial drone. The chapter?s goal is first to tackle in detail the development of a custom-designed lightweight GPR by approaching interplay between hardware and software radio on an SDR platform. The SDR-based GPR system results on a much lighter sensing device compared against the conventional GPR systems found in the literature and with the capability of re-configuration in real-time for different landmines and terrains, with the capability of detecting landmines under terrains with different dielectric characteristics. Secondly, the chapter introduce the integration of the SDR-based GPR into an autonomous drone by describing the mechanical integration, communication system, the graphical user interface (GUI) together with the landmine detection and geo-mapping. This chapter approach completely the hardware and software implementation topics of the on-board GPR system given first a comprehensive background of the software-defined radar technology and second presenting the main features of the Tx and Rx modules. Additional details are presented related with the mechanical and functional integration of the GPR into the UAV system.",book:{id:"5905",slug:"robots-operating-in-hazardous-environments",title:"Robots Operating in Hazardous Environments",fullTitle:"Robots Operating in Hazardous Environments"},signatures:"Manuel Ricardo Pérez Cerquera, Julian David Colorado Montaño\nand Iván Mondragón",authors:[{id:"177422",title:"Dr.",name:"Julian",middleName:null,surname:"Colorado",slug:"julian-colorado",fullName:"Julian Colorado"},{id:"197884",title:"Prof.",name:"Ivan",middleName:null,surname:"Mondragon",slug:"ivan-mondragon",fullName:"Ivan Mondragon"},{id:"199958",title:"Prof.",name:"Manuel",middleName:null,surname:"Perez",slug:"manuel-perez",fullName:"Manuel Perez"}]},{id:"15855",title:"Kinematics of AdeptThree Robot Arm",slug:"kinematics-of-adeptthree-robot-arm",totalDownloads:14668,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"152",slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Adelhard Beni Rehiara",authors:[{id:"29287",title:"Dr.",name:"Adelhard",middleName:"Beni",surname:"Rehiara",slug:"adelhard-rehiara",fullName:"Adelhard Rehiara"}]},{id:"62978",title:"Intelligent Robotic Perception Systems",slug:"intelligent-robotic-perception-systems",totalDownloads:2443,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Robotic perception is related to many applications in robotics where sensory data and artificial intelligence/machine learning (AI/ML) techniques are involved. Examples of such applications are object detection, environment representation, scene understanding, human/pedestrian detection, activity recognition, semantic place classification, object modeling, among others. Robotic perception, in the scope of this chapter, encompasses the ML algorithms and techniques that empower robots to learn from sensory data and, based on learned models, to react and take decisions accordingly. The recent developments in machine learning, namely deep-learning approaches, are evident and, consequently, robotic perception systems are evolving in a way that new applications and tasks are becoming a reality. Recent advances in human-robot interaction, complex robotic tasks, intelligent reasoning, and decision-making are, at some extent, the results of the notorious evolution and success of ML algorithms. This chapter will cover recent and emerging topics and use-cases related to intelligent perception systems in robotics.",book:{id:"7227",slug:"applications-of-mobile-robots",title:"Applications of Mobile Robots",fullTitle:"Applications of Mobile Robots"},signatures:"Cristiano Premebida, Rares Ambrus and Zoltan-Csaba Marton",authors:[{id:"203409",title:"Ph.D.",name:"Cristiano",middleName:null,surname:"Premebida",slug:"cristiano-premebida",fullName:"Cristiano Premebida"},{id:"254880",title:"Dr.",name:"Rares",middleName:null,surname:"Ambrus",slug:"rares-ambrus",fullName:"Rares Ambrus"},{id:"254881",title:"Dr.",name:"Zoltan-Csaba",middleName:null,surname:"Marton",slug:"zoltan-csaba-marton",fullName:"Zoltan-Csaba Marton"}]},{id:"67705",title:"Advanced UAVs Nonlinear Control Systems and Applications",slug:"advanced-uavs-nonlinear-control-systems-and-applications",totalDownloads:1971,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Recent development of different control systems for UAVs has caught the attention of academic and industry, due to the wide range of their applications such as in surveillance, delivery, work assistant, and photography. In addition, arms, grippers, or tethers could be installed to UAVs so that they can assist in constructing, transporting, and carrying payloads. In this book chapter, the control laws of the attitude and position of a quadcopter UAV have been derived basically utilizing three methods including backstepping, sliding mode control, and feedback linearization incorporated with LQI optimal controller. The main contribution of this book chapter would be concluded in the strategy of deriving the control laws of the translational positions of a quadcopter UAV. The control laws for trajectory tracking using the proposed strategies have been validated by simulation using MATLAB®/Simulink and experimental results obtained from a quadcopter test bench. Simulation results show a comparison between the performances of each of the proposed techniques depending on the nonlinear model of the quadcopter system under investigation; the trajectory tracking has been achieved properly for different types of trajectories, i.e., spiral trajectory, in the presence of unknown disturbances. Moreover, the practical results coincided with the results of the simulation results.",book:{id:"7792",slug:"unmanned-robotic-systems-and-applications",title:"Unmanned Robotic Systems and Applications",fullTitle:"Unmanned Robotic Systems and Applications"},signatures:"Abdulkader Joukhadar, Mohammad Alchehabi and Adnan Jejeh",authors:null}],onlineFirstChaptersFilter:{topicId:"22",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82223",title:"Biomechanical Design Principles Underpinning Anthropomorphic Manipulators",slug:"biomechanical-design-principles-underpinning-anthropomorphic-manipulators",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.105434",abstract:"The biomechanical design of an artificial anthropomorphic manipulator is the focus of many researchers in diverse fields. Current electromechanical artificial hands are either in the research stage, expensive, have patents, lack severely in function, and/or are driven by robotic/mechanical principles, which tend to ignore the biological requirements of such designs. In response to the challenges addressed above this chapter discusses the potential of current technology and methods used in design to bridge the chasm that exists between robot manipulators and the human hand. This chapter elucidates artificial anthropomorphic manipulator design by outlining biomechanical concepts that contribute to the function, esthetics and performance of artificial manipulators. This chapter addresses joint stabilization, tendon structures and tendon excursion in artificial anthropomorphic manipulators.",book:{id:"11455",title:"Recent Advances in Robot Manipulators",coverURL:"https://cdn.intechopen.com/books/images_new/11455.jpg"},signatures:"Mahonri William Owen and Chikit Au"},{id:"82056",title:"Learning Robotic Ultrasound Skills from Human Demonstrations",slug:"learning-robotic-ultrasound-skills-from-human-demonstrations",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.105069",abstract:"Robotic ultrasound system plays a vital role in assisting or even replacing sonographers in some cases. However, modeling and learning ultrasound skills from professional sonographers are still challenging tasks that hinder the development of ultrasound systems’ autonomy. To solve these problems, we propose a learning-based framework to acquire ultrasound scanning skills from human demonstrations1. First, ultrasound scanning skills are encapsulated into a high-dimensional multi-modal model, which takes ultrasound images, probe pose, and contact force into account. The model’s parameters can be learned from clinical ultrasound data demonstrated by professional sonographers. Second, the target function of autonomous ultrasound examinations is proposed, which can be solved roughly by the sampling-based strategy. The sonographers’ ultrasound skills can be represented by approximating the limit of the target function. Finally, the robustness of the proposed framework is validated with the experiments on ground-true data from sonographers.",book:{id:"10823",title:"Cognitive Robotics",coverURL:"https://cdn.intechopen.com/books/images_new/10823.jpg"},signatures:"Miao Li and Xutian Deng"},{id:"82057",title:"An Episodic-Procedural Semantic Memory Model for Continuous Topological Sensorimotor Map Building",slug:"an-episodic-procedural-semantic-memory-model-for-continuous-topological-sensorimotor-map-building",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.104818",abstract:"For humans to understand the world around them, learning and memory are two cognitive processes of the human brain that are deeply connected. Memory allows information to retain and forms an experiences reservoir. Computational models replicating those memory attributes can lead to the practical use of robots in everyday human living environments. However, constantly acquiring environmental information in real-world, dynamic environments has remained a challenge for many years. This article proposes an episodic-procedure semantic memory model to continuously generate topological sensorimotor maps for robot navigation. The proposed model consists of two memory networks: i) episodic-procedural memory network (EPMN) and ii) semantic memory network (SMN). The EPMN comprises an Incremental Recurrent Kernel Machines (I-RKM) that clusters incoming input vectors as nodes and learns the activation patterns of the nodes for spatiotemporal encoding. The SMN then takes neuronal activity trajectories from the EPMN and task-relevant signals to update the SMN and produce more compact representations of episodic experience. Thus, both memory networks prevent catastrophic forgetting by constantly generating nodes when the network meets new inputs or updating node weights when the incoming input is similar to previously learned knowledge. In addition, idle or outlier nodes will be removed to preserve memory space.",book:{id:"10823",title:"Cognitive Robotics",coverURL:"https://cdn.intechopen.com/books/images_new/10823.jpg"},signatures:"Wei Hong Chin, Naoyuki Kubota and Chu Kiong Loo"},{id:"81922",title:"Skill Acquisition for Resource-Constrained Mobile Robots through Continuous Exploration",slug:"skill-acquisition-for-resource-constrained-mobile-robots-through-continuous-exploration",totalDownloads:18,totalDimensionsCites:0,doi:"10.5772/intechopen.104996",abstract:"We present a cognitive mobile robot that acquires knowledge, and autonomously learns higher-level abstract capabilities based on play instincts, inspired by human behavior. To this end, we (i) model skills, (ii) model the robot’s sensor and actuator space based on elementary physical properties, and (iii) propose algorithms inspired by humans’ play instincts that allow the robot to autonomously learn the skills based on its sensor and actuator capabilities. We model general knowledge in the form of competencies (skills) of the mobile robot based on kinematic properties using physical quantities. Thus, by design, our approach has the potential to cover very generic application domains. To connect desired skills to the primitive capabilities of the robot’s sensors and actuators, it playfully explores the effects of its actions on its sensory input, thus autonomously learning relations and dependencies and eventually the desired skill. KnowRob is used for knowledge representation and reasoning, and the robot’s operation is based on ROS. In the experiments, we use a millirobot, sized 2 cm2, equipped with two wheels, motion, and distance sensors. We show that our cognitive mobile robot can successfully and autonomously learn elementary motion skills based on a playful exploration of its wheels and sensors.",book:{id:"10823",title:"Cognitive Robotics",coverURL:"https://cdn.intechopen.com/books/images_new/10823.jpg"},signatures:"Markus D. Kobelrausch and Axel Jantsch"},{id:"81693",title:"The Neo-Mechanistic Model of Human Cognitive Computation and Its Major Challenges",slug:"the-neo-mechanistic-model-of-human-cognitive-computation-and-its-major-challenges",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.104995",abstract:"The neo-mechanistic theory of human cognition is currently one of the most accepted major theories in fields, such as cognitive science and cognitive neuroscience. This proposal offers an account of human cognitive computation, and it has been considered by its proponents as revolutionary and capable of integrating research concerning human cognition with new evidence provided by fields of biology and neuroscience. However, some complex cognitive capacities still present a challenge for explanations constructed by using this theoretical structure. In this chapter, I make a presentation of some of the central tenets of this framework and show in what dimensions it helps our understanding of human cognition concerning aspects of capacities, such as visual perception and memory consolidation. My central goal, however, is to show that to understand and explain some particular human cognitive capacities, such as self-consciousness and some conscious informal reasoning and decision making, the framework shows substantial limitations. I conclude the chapter by suggesting that to fully understand human cognition we will need much more than what the neo-mechanistic framework is actually able to provide.",book:{id:"10823",title:"Cognitive Robotics",coverURL:"https://cdn.intechopen.com/books/images_new/10823.jpg"},signatures:"Diego Azevedo Leite"},{id:"81719",title:"Service Robots in Healthcare Settings",slug:"service-robots-in-healthcare-settings",totalDownloads:21,totalDimensionsCites:0,doi:"10.5772/intechopen.104640",abstract:"Robots will play a part in all aspects of healthcare. The presence of service robots in healthcare demands special attention, whether it is in the automation of menial labour, prescription distribution, or offering comfort. In this chapter, we examine the several applications of healthcare-oriented robots in the acute, ambulatory and at-home settings. 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The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}}]}},subseries:{item:{id:"3",type:"subseries",title:"Bacterial Infectious Diseases",keywords:"Antibiotics, Biofilm, Antibiotic Resistance, Host-microbiota Relationship, Treatment, Diagnostic Tools",scope:"