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:"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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"212",leadTitle:null,fullTitle:"Energy Storage in the Emerging Era of Smart Grids",title:"Energy Storage in the Emerging Era of Smart Grids",subtitle:null,reviewType:"peer-reviewed",abstract:'Reliable, high-efficient and cost-effective energy storage systems can undoubtedly play a crucial role for a large-scale integration on power systems of the emerging "distributed generation" (DG) and for enabling the starting and the consolidation of the new era of so called smart-grids. A non exhaustive list of benefits of the energy storage properly located on modern power systems with DG could be as follows: it can increase voltage control, frequency control and stability of power systems, it can reduce outages, it can allow the reduction of spinning reserves to meet peak power demands, it can reduce congestion on the transmission and distributions grids, it can release the stored energy when energy is most needed and expensive, it can improve power quality or service reliability for customers with high value processes or critical operations and so on.\nThe main goal of the book is to give a date overview on: (I) basic and well proven energy storage systems, (II) recent advances on technologies for improving the effectiveness of energy storage devices, (III) practical applications of energy storage, in the emerging era of smart grids.',isbn:null,printIsbn:"978-953-307-269-2",pdfIsbn:"978-953-51-6057-1",doi:"10.5772/737",price:139,priceEur:155,priceUsd:179,slug:"energy-storage-in-the-emerging-era-of-smart-grids",numberOfPages:494,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"8cd6021285906516c727802d02ce0954",bookSignature:"Rosario Carbone",publishedDate:"September 22nd 2011",coverURL:"https://cdn.intechopen.com/books/images_new/212.jpg",numberOfDownloads:105688,numberOfWosCitations:89,numberOfCrossrefCitations:23,numberOfCrossrefCitationsByBook:14,numberOfDimensionsCitations:106,numberOfDimensionsCitationsByBook:16,hasAltmetrics:1,numberOfTotalCitations:218,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 19th 2010",dateEndSecondStepPublish:"November 16th 2010",dateEndThirdStepPublish:"March 30th 2011",dateEndFourthStepPublish:"April 22nd 2011",dateEndFifthStepPublish:"June 21st 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"11592",title:"Prof.",name:"Rosario",middleName:null,surname:"Carbone",slug:"rosario-carbone",fullName:"Rosario Carbone",profilePictureURL:"https://mts.intechopen.com/storage/users/11592/images/1808_n.jpg",biography:"Dr. Rosario Carbone was born in Italy in 1965. In 1990., he received his degree on Electrical Engineering, from University of Calabria, Italy. In 1995., he received his Ph.D. on Electrical Engineering, from University “Federico II” of Naples, Italy. In 1995., he became a researcher on electrical power systems, at the University of Neaples, Italy. At the moment, he is an Associate Professor on electrical power systems, at the University “Mediterranea” of Reggio Calabria – Italy. His educational activities mainly concern electrical power systems, power electronics and electrical safety. His research activities deal with: (I) power electronic apparatus with high performances; (II) analysis of electrical power systems in presence of power electronic apparatus; (III) high performance distributed generation plants from renewables. Rosario Carbone is author of about 70 papers; he won a “best paper award” at the IEEE International Conference “I.C.H.Q.P. 2000”, Orlando, USA .",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Reggio Calabria",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"771",title:"Sustainability Science",slug:"sustainability-science"}],chapters:[{id:"20361",title:"Electrochemical Energy Storage",doi:"10.5772/23452",slug:"electrochemical-energy-storage",totalDownloads:2840,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:1,abstract:null,signatures:"Pier Luigi Antonucci and Vincenzo Antonucci",downloadPdfUrl:"/chapter/pdf-download/20361",previewPdfUrl:"/chapter/pdf-preview/20361",authors:[{id:"52087",title:"Prof.",name:"Pier Luigi",surname:"Antonucci",slug:"pier-luigi-antonucci",fullName:"Pier Luigi Antonucci"},{id:"52095",title:"Dr.",name:"Vincenzo",surname:"Antonucci",slug:"vincenzo-antonucci",fullName:"Vincenzo Antonucci"}],corrections:null},{id:"20362",title:"Supercapacitor-Based Electrical Energy Storage System",doi:"10.5772/18667",slug:"supercapacitor-based-electrical-energy-storage-system",totalDownloads:5389,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:1,abstract:null,signatures:"Masatoshi Uno",downloadPdfUrl:"/chapter/pdf-download/20362",previewPdfUrl:"/chapter/pdf-preview/20362",authors:[{id:"32176",title:"Dr.",name:"Masatoshi",surname:"Uno",slug:"masatoshi-uno",fullName:"Masatoshi Uno"}],corrections:null},{id:"20363",title:"Rotor Design for High-Speed Flywheel Energy Storage Systems",doi:"10.5772/18359",slug:"rotor-design-for-high-speed-flywheel-energy-storage-systems",totalDownloads:10641,totalCrossrefCites:8,totalDimensionsCites:14,hasAltmetrics:0,abstract:null,signatures:"Malte Krack, Marc Secanell and Pierre Mertiny",downloadPdfUrl:"/chapter/pdf-download/20363",previewPdfUrl:"/chapter/pdf-preview/20363",authors:[{id:"31261",title:"Dr.",name:"Pierre",surname:"Mertiny",slug:"pierre-mertiny",fullName:"Pierre Mertiny"},{id:"42836",title:"Mr.",name:"Malte",surname:"Krack",slug:"malte-krack",fullName:"Malte Krack"},{id:"42837",title:"Dr.",name:"Marc",surname:"Secanell",slug:"marc-secanell",fullName:"Marc Secanell"}],corrections:null},{id:"20364",title:"An Application of Genetic Fuzzy Systems to the Operation Planning of Hydrothermal Systems",doi:"10.5772/17847",slug:"an-application-of-genetic-fuzzy-systems-to-the-operation-planning-of-hydrothermal-systems",totalDownloads:2001,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Ricardo de A. 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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).
Recently, the space industry has pointed out that in the past 5 years, the commercial market has been driving the advancement of satellite technology. Lockheed Martin is building commercial satellites (e.g., Hellas-sat series) with advanced on-board processing capabilities for the Saudi Arabian [1]. Hellas satellites probably will be the first commercial HTS with a very advanced digital processor on-board. The focus of this chapter will be on commercial satellite systems for communication applications, and a comparison study between commercial HTS and typical satellites systems conducted by Inmarsat will be provided [2].
For communication applications, commercial satellite systems have been categorized as mobile satellite services (MSSs), fixed satellite services (FSSs), broadcast satellite services (BSSs), and high-throughput satellite (HTS) services. Depending on the services, satellite payload architecture will be designed to meet the specified requirements for that service. Basically, satellite payload architecture can be classified into four categories: (1) analog bent-pipe satellite (ABPS); (2) digital bent-pipe satellite (DBPS); (3) advanced digital bent-pipe satellite using digital channelizer and beamformer (AdDBPS-DCB); and (4) advanced regenerative on-board processing satellite (AR-OBPS). This chapter provides an overview of these payload architectures and presents two satellite system architectures using AdBPS-DCBS and AR-OBPS payloads for the fifth-generation cellular phone (5G) applications.
The chapter is organized as follows: Section 2 provides a comparison between commercial HTS and typical satellite systems; Section 3 discusses the typical satellite network topologies; Section 4 presents an overview of legacy ADPS transponder, existing DBPS transponder, AdBPS-DCBS transponder, and AR-OBPS satellite system; Section 5 discusses the use of AdBPS-DCBS transponder and AR-OBPS payloads for the fifth-generation cellular phone (5G) applications; and Section 6 concludes the chapter with a summary and brief discussion of way forward.
Typical and regular commercial satellites are operating in C-band, Ku-band, and Ka-band with downlink frequencies approximately at 4, 12, and 40 GHz, respectively. For C-band, Ku-band, and Ka-band, the spectrum bandwidths available by geostationary orbital position are 500 MHz, 500 MHz, and 3.5 GHz, respectively. Typical antenna types for these regular commercial satellites are pointed antenna type with a single beam. Typical diameters for these pointed antennas are (a) greater than 1.8 m for C-band; (b) 0.9–1.2 m for Ku-band; and (c) 0.6–1.2 m for Ka-band satellite. Figure 1(a) illustrates a typical regular commercial satellite.
Typical commercial satellites and HTS configurations.
Typical HTSs are usually also operating in Ku-band and Ka-band with the same downlink frequencies as the regular satellites except that they employ multiple pointed beam as oppose to a single-pointed beam. Figure 1(b) describes a multiple beam HTS system. The salient feature of multiple beams is the frequency reuse. The frequency reuse is defined as the number of times a satellite can reuse the same spectrum and frequencies. However, high frequency reuse factor can cause potential cochannel interference or an increase in carrier-to-interference power ratio (CIR or C/I). IMMARSAT has reported that a reuse factor of 5–30 is possible with multiple spot beams employed by commercial HTS. Depending on the number of beams implemented on-board of the satellite, the cost for HTS can be twice of the cost for a regular satellite. But, the cost per bit for HTS is much lower than the regular satellite. HTS is a preferred option for point-to-point services, for example, beyond line-of-sight (BLOS) cellular phone services. Table 1 provides a summary of the comparison of HTS and regular commercial satellites [2].
Comparison factor | Typical regular commercial satellite | Typical high-throughput satellite (HTS) | Remark |
---|---|---|---|
Operational frequency band | C-band, Ku-band, Ka-band | Ku-band, Ka-band | It should be noted that for data presented here, all satellites and supply are not equal; various technical, regulatory, and commercial parameters come into play when comparing the two-type satellites. Data collected from IMMARSAT. Source: see [2] |
Throughput capability (Gbps) | ~1–10 | ~5–300+ (with frequency reuse in multiple spot beam) | |
Typical cost including launch (USD) | ~200–300 | ~300–500 (cost can be twice of regular satellite) | |
Advantages | Wide coverage; preferred solution for point-to-multipoint communication | Higher bandwidth/lower cost per bit; preferred option for point-to-point services | |
Disadvantages | Limited supply available; lower spectrum efficiency for an equivalent frequency | Higher upfront costs; difficult to find enough customers to fill each of the beams |
Comparison of typical commercial satellites and HTS.
This section describes the most commonly used satellite network topologies, namely “Star” satellite network (Section 3.1) and “Mesh” satellite network (Section 3.2).
A typical commercial satellite network topology consists of an uplink from a central anchor station (aka satellite Gateway or satellite Hub) to a satellite and a downlink from the satellite to users. Users can be mobile or fixed users. Mobile users can be located in an airplane, a boat, or a car. Fixed users can be located in a building or a cellular base station. The “star” satellite network is derived from a spoke-hub distribution paradigm in computer networks, where one central hub serves as a conduit to transmit messages among network users [3]. Thus, for star satellite networks, all communications will be passed through a satellite gateway. As shown in Figure 2, if Mobile User 1 wants to talk to Mobile User 2, Mobile User 1 needs to send its messages to the satellite gateway (yellow lines), and satellite gateway relays that messages to Mobile User 2 (red lines).
Typical “star” satellite network.
The “mesh” satellite network topology is derived from a local network topology, where the network nodes are corrected to each other directly, dynamically, and nonhierarchically to as many other nodes as possible [4]. In this network topology, the network nodes can cooperate with one another to route data from one user to another user efficiently. Hence, for mesh satellite network, Mobile User 1 can talk to fixed user directly without going through the satellite gateway (solid lines), and Mobile User 2 can also talk to the fixed user directly (dash lines). Any one of the user within the network can send the messages to a terrestrial network through the red lines representing uplink and downlink between the satellite gateway and the satellite (Figure 3).
Typical “mesh” satellite network.
Star satellite network topology does not require advanced satellite payload processing on-board and multiple beam, but mesh satellite network requires advanced on-board processing and multiple beam allowing one user to communicate to another user automatically and effectively. Section 4 discusses various satellite payload architectures used in regular satellite and HTS for star and mesh satellite network applications.
This section presents an overview of legacy, existing, and advanced satellite payload architectures. Section 4.1 presents legacy ABPS payload architecture, Section 4.2 provides a description of a typical existing DBPS payload architecture, Section 4.3 discusses AdDBPS-DCB payload architecture, and Section 4.4 provides an overview of AR-OBPS payload architecture.
A typical legacy ABPS payload architecture is depicted in Figure 4, where the payload has multiple beam antennas (MBAs) using parabolic dishes. For this architecture, the RF signal is received at the satellite payload and amplifies by a low noise amplifier (LNA) for increased received signal-to-noise power ratio (SNR). The RF signal with increased SNR is downconverted (D/C) to an intermediate frequency (IF) and processed by an IF filter to clean up the signal from adjacent interference and out-of-band noise. The clean-up signal is then (a) routed to the proper downlink port by an IF analog switching circuit and upconverted (U/C) to RF, (b) combined by a multiplexer (MUX), and (c) amplified by a high-power amplifier (HPA) for downlink transmission.
Legacy ABPS payload architecture.
As illustrated in Figure 5, there are two options for the D/C, namely Option 1 (see Figure 5(a)) is a double downconverter using two local oscilators (LOs) to downconvert RF signal to IF signal with stable and low phase noise, and Option 2 (see Figure 5(b)) is single downconverter using a LO downconverting RF signal directlty to an IF signal. Option 1 is being used in many legacy, existing, and advanced satellite payloads. Option 2 is mostly used in advanced satellite payloads.
Options for RF downconversion and associated LO’s phase noise.
Figure 5(c) shows commercial-of-the-shelf (COTS) phase noise characteristics for typical LOs operating at X-band, Ku-band, and Ka-band. X-band, Ku-band, and Ka-band illustrated in this figure correspond to 7–11.2, 12–18, and 26.5–40 GHz, respectively. The main advantages of Option 2 using single downconversion are its low cost, small size, and low power consumption (also known as small SWAP-C). This option uses the smallest number of external components as compared to Option 1 using double downconversion, which is also known as super heterodyne receiver [5]. However, Option 2 suffers amplitude and phase imbalances caused by imperfect references associated with I-Q components, direct current (DC) signal due to self-mixing, and flicker noise.1 Option 1 does not suffer from these problems and offers excellent selectivity and sensitivity, that is, better rejection of adjacent interferences. Option 1’s disadvantages are the integration complexity and high SWAP-C.
In satellite electronic communications, MUX is a multiplexer, which is a device that selects several (multiple) analog (or digital) input signals and outputs a single signal. Figure 6(a) describes a functional MUX (aka multiplexer) circuit. On the contrary, Figure 6(b) depicts a DEMUX (aka demultiplexer), which is an electronic device that sends a single input signal to multiple signal outputs.
Functional block diagrams of MUX and DEMUX.
Figure 7 presents an existing DBPS payload architecture using on-board digital channelizer. Similar to analog payload, there are two options for the RF-to-IF downconversion process. Double-downconversion process is typically used for digital bent-pipe payload architecture.
Existing DBPS payload architecture.
Figure 8 depicts typical RF-to-IF (or baseband) downconversion and digitization and sampling processes for a commercial DBPS payload architecture. The RF-to-IF process shown in this figure uses Option 1, double downconversion, and the digitization and sampling process employing bandpass sampling with digital quadrature technology [6]. The RF bandwidth (BW) associated with the RF bandpass filter (BPF) is selected to match with an over channel bandwidth (e.g., a maximum of 500 MHz for Ku-band). The automated gain control (AGC) is designed to maintain a constant power over the specified channel bandwidth. There are several advantages associated with bandpass sampling with digital quadrature techniques, including (a) no phase and amplitude imbalances; (b) digital finite impulse response (FIR) filters are flexible and computational complexity with linear phase introducing a constant group delay; (c) only one A/D converter is required (less weight and power); and (d) when the sampling period is set at one-quarter of the carrier frequency, the reference in-phase and quadrature components reduce to an alternating sequence between I-channel and Q-channel [6].
Typical R/F downconversion and digitization processing approach.
As shown in Figure 9, the key design issue associated with the digitization and sampling processing is the selection of required number of bits of the analog-to-digital (A/D) conversion to (1) achieve optimum loading factor (LF) and (2) minimize the quantization noise. The LF is defined as the root mean square (RMS) of the total input signal voltage-to-A/D converter saturation voltage ratio. The total input signal voltage includes desired signal voltage (S) plus noise voltage (N) plus interference voltage (I). Figure 10 illustrates an optimum LF as a function of number of bit of a typical A/D converter. As an example, for 4-bit, the optimum LF is about 0.4. In conjunction with LF, the number of bit should be selected to maximize the signal-to-quantization noise ratio (SQNR) using the following relationship:2
Existing digitization and sampling processing using bandpass sampling with digital quadrature technique.
Optimum LF as a function of number of bit of A/D converter.
As an example, when
The key feature of DBPS payloads is the flexibility of the digital channelizer. Current digital technologies allow for the implementation of robust and reconfigurable digital channelizer adapting to require the number of users and associated users’ data rates. A typical flexible digital channelizer using polyphase/discrete Fourier transform (DFT) technology is shown in Figure 11.
Typical digital channelizer using polyphase/DFT technology.
As shown in Figure 11, the heart of a typical digital channelizer is a polyphase-filter network (or simply a polyphase network) and a DFT processor. A typical polyphase network with a DFT processor is described in Figure 12. The polyphase network consists of a set of NC digital filters with transfer function H0, H1..., HNc-1, which is obtained by shifting a basic low pass complex filter function along the frequency axis [7]. As an example, for a typical 500 MHz channel bandwidth, assuming for a typical user data rate of 4 MHz and a guardband of 1 MHz, digital channelizer, NC = 500/(4 + 1) = 100, that is, the number of filter is 100, and each has a total of 5 MHz bandwidth. A change in sampling frequency by a factor of NC can be introduced, thus allowing the circuit in different paths of the polyphase network to operate at lower frequency than the original sampling frequency. A practical implementation of a high-throughput low-latency polyphase channelizer can be found in [8, 9].
Typical Polyphase/DFT Technology.
Figure 12 shows an example of five input signals, namely S1, S2, S3, S4, and S5, and the channelizer will select signal interest by filtering out the other signals. As an example, the signal line with the filter transfer function of H0 filters out S2, S3, S4, and S5 and sends S1 as an output signal.
For a typical commercial HTS system architecture, it usually requires on-board multiple beam phase array (PA) antenna with associated adaptive digital beamformer network (DBF) for spot beamforming and frequency reusing of the spot beams when the beams are not located near each other. Figure 13 describes a typical AdDBPS-DCB payload architecture, where the digital channelizer is combined with a DBF to make a “digital channelizer and beamformer” (DCB) [10, 11, 12]. For this payload architecture, the key feature that differentiates this architecture with the ones discussed above is the combined digital channelizer using polyphase network/DFT processor and DBF (PolyN/DFT-DBF).
AdDBPS-DCB payload architecture.
As pointed out in [10, 11, 12], DCB architecture shown in Figure 13 can be designed to (1) form individual beams for each active receive and transmit communication channels; (2) adaptively generate channel beam steering weights to dynamically vary the bandwidth, location, and shape of each beam based on traffic demands and the locations of other, potentially interfering beams avoiding adjacent channel interference; (3) use digital beamforming weight calibration to compensate for the temporal and thermal phase and amplitude response variations inherent in analog multibeam phased array antennas; and (4) adjust the gain of individual receive-and-transmit channel beams automatically to compensate for propagation path and analog payload response variations. In general, there are two possible DCB implementation approaches, namely DCB Approach 1 and DCB Approach 2 [13]. Figure 14 describes the DCB Approach 1 for processing the uplink signals, where the uplink signals are individually processed by the digital channelizer (i.e., PolyN/DFT processing) and DBF independently and separately. DCB Approach 1 requires a larger computational load because each DBF processes all the user link bandwidth (e.g., S1, S2, S3, S4, and S5 in Figure 12) at all times to form multiple beams.
DCB Approach 1: PolyN/DFT and DBFN individual processing.
DCB Approach 2 is shown in Figure 15, where DCB utilizes an unified processing approach with each DBF processes only the bandwidth corresponding to a beam (S1 in Figure 12) at normal times. During anomaly operation condition (e.g., natural disaster event), when the bandwidth has to be reassigned to specific areas, the arithmetic load on DBF can be reduced by implementing multiple DBFs, with each capable of processing a bandwidth narrower than that assigned to a beam (i.e., smaller channel unit). This approach enables a reduction in wasteful arithmetic resource usage on bandwidth.
DCB Approach 2: Unified and combined PolyN/DFT and DBFN individual processing.
If one defines the number of multipliers, D implemented in each Tx/Rx DBF as C/fop, where C is the computational load of a DBF (multiplications/sec), and fop is the operation frequency of the multiplier. Let us compare D calculations between DCB Approach 1 and DCB Approach 2. Let us assume the following parameters:
and that for DCB Approach 2 configuration becomes [13]:
The latter calculation assumes an ideal case in which DBF network (DFBN) processing is performed on a channel-by-channel basis. The complexity of DCB Approach 2 configuration is 10 times less complex than DCB Approach 1.
As pointed out in [12], the DBFN when coupled with a digital channelizer (aka DCB) offered more capabilities with many advantages. Nguyen et al. [14] developed a computer simulation model of a typical DBFN in MATLAB and presented simulation results for X, Ku, and Ka BFNs using 60-element, 104-element, and 149-element, respectively. Figure 16 is an extracted Ka-band BFN result showing the achievable antenna gain of 45.5 dB at 3-dB beamwidth of 0.9°. For practical applications, the DBFN will shape the beam size depending on the coverage area and desired number of beams. Nguyen et al. [14] pointed out that for 2.5° coverage area and the desired number of beams of 7, the minimum 3-dB beamwidth of 1.1° is required. Nguyen et al. [14] also pointed out that DCB can provide a significant increase in frequency reuse, where the frequency reuse is defined as the number of times a satellite can reuse the same spectrum and frequencies. High frequency reuse factor can cause potential cochannel interference (CCI) that results in a decrease in carrier-to-interference power ratio [aka (C/I) CCI]. As pointed out in [14], for dynamic allocation using real-time allocation of beams so that the coverage radius of a cell is equal to the satellite pointing error, assuming satellite pointing error of 0.02 degree pointing error, the (C/I)CCI is about 25 dB for frequency reuse factor 40 [14].
Antenna beamwidth and gain of a notional Ka-band DBFN with 12-bit quantization [
Figure 17 depicts a potential future AR-OBPS payload architecture [10]. The payload includes (1) a typically set of digitized analog multiple beam antenna (MBA) input signals, digitally frequency division demultiplex each input signal to produce single carrier per channel (SCPC) signal data and demodulate and decode individual traffic channels to recover the original information bits transmitted on the uplink; (2) a set of digitized analog multibeam phase array antenna (MB-PAa) input signals, digitally frequency division demultiplex each input signal to produce SCPC signal data and demodulate and decode individual traffic channels to recover the original information bits transmitted on the uplink; and (3) fast packet switches are typically employed at the AR-OBPS payload’s core to realize statistical multiplexing gains by efficiently packing and moving data through the switch and onto the downlink in bursty uplink transmission applications. Moreover, the digital bandwidth (in Hz) through the AR-OBPS switch is at least 25 times less3 than that supported by an equivalent (pre-demodulation) digital baseband switch at the center of a DC- or DCB-based system. AR-OBPS payload can also support digital beamforming, following the frequency division demultiplexing operation, if a phased array is employed in place of the analog MBA. On the secondary (output) side of the switch, each user’s binary information is channel encoded and modulated onto a carrier. The modulated carrier data thus produced are multiplexed, digital-to-analog converted, and passed through an analog reconstruction filter to generate output signals for the transmit portion of the communication payload. The channel codes and modulations employed on the uplink (input) communication channels clearly do not need to be the same as the channel codes and modulations used on the transmitted downlink channels. Hence, an AR-OBPS payload can serve as a “translator” facilitating single-hop communications between terminals employing different link protocols. However, if either the digital multichannel demultiplexer (DMCD), demodulator, decoder, or digital multichannel multiplexer (DMCM) encoder modulator, multiplexer (MCEM2) functions are implemented in ASICs to minimize size-weight-and-power (SWaP), then the AR-OBPS system becomes somewhat inflexible, unable to support either uplink or downlink terminals, respectively, using communication protocols differing from those for which the AR-OBPS was specifically designed. For this reason, AR-OBPS systems are typically employed in support of “private networks” in which the communication satellite service provider only accommodates terminals designed to work on the provider’s network. Iridium and Spaceway are two examples of commercial AR-OBPS-based communication satellite systems.
AR-OBPS payload architecture.
Sections 5.1 and 5.2 present a notional satellite system architecture using AdBPS-DCBS satellite payload and AR-OBPS satellite system architecture for 5G cellular phone applications, respectively.
AdBPS-DCBS satellite payload can be used to support 5G users. There are potentially two satellite system architecture options for using AdBPS-DCBS satellite payload to support 5G mobile user equipment (aka 5G-UE), namely AdBPS-DCBS Option 1 and AdBPS-DCBS Option 2. For AdBPS-DCBS Option 1, the AdBPS-DCBS satellite provides communication services directly to 5G-UEs. While in AdBPS-DCBS Option 2, the satellite provides services to 5G-UEs through the 5G relay nodes (RNs). Figure 18 illustrates the AdBPS-DCBS satellite system architecture for (a) AdBPS-DCBS Option 1 and (b) AdBPS-DCBS Option 2 [15].
AdDBPS-DCB satellite system architectures for supporting 5G users.
Figure 18(a) shows that the AdBPS-DCBS satellite requires new radio (NR) interfaces between (1) AdBPS-DCBS satellite and terrestrial gateway (GW) and (2) AdBPS-DCBS satellite and 5G-UEs. In addition, it is also required a 5G narrow-band (gNB) processing station to process the 5G signals from the next generation core (NGC) network before passing the 5G data to public data network.
Similar to AdBPS-DCBS satellite payload, AR-OBPS satellite payload can also be used to support 5G users. There are also two satellite system architecture options for using AR-OBPS payload to support 5G mobile user equipment, namely AR-OBPS Option 1 and AR-OBPS Option 2. For AR-OBPS Option 1, the AR-OBPS satellite provides communication services directly to 5G-UEs. For AR-OBPS Option 2, the satellite provides services to 5G-UEs through the 5G RNs. Figure 19 describes these two AR-OBPS architecture options, namely (a) for AR-OBPS Option 1 and (b) for AR-OBPS Option 2. For these two system architecture options, the gNB processing is now incorporated into the AR-OBPS satellite payload and no longer required for the ground system. The GW now can pass the 5G data directly to the NGC. The decoding-demodulation and encoding-modulation processing on-board of the satellite will be designed to align with the 5G waveform specifications, including 5G modulation and coding schemes.
AR-OBPS satellite system architectures for supporting 5G users.
Figure 19(a) shows that the AR-OBPS satellite also requires NR interfaces between (1) AR-OBPS satellite and GW and (2) AR-OBPS satellite and 5G-UEs. Similar to AdBPS-DCBS satellite system architecture options, the NR interfaces between the AR-OBPS satellite and 5G-UEs are new. Since the gNB processing is now placed at AR-OBPS satellite payload, the NR interfaces between AR-OBPS satellite and 5G-UEs are not the same as the AdBPS-DCBS satellite and 5G-UEs. To show the differences between the two, Figures 19(a) and (b) use Sat-NG-C and Sat-NG-U to indicate the new radio interface between (1) terrestrial GW-NGC-and-AR-OBPS satellite and (2) AR-OBPS satellite-and-terrestrial GW-NGC, respectively.
This chapter uses a top-down approach for providing an overview of legacy, existing, and future advanced satellite payload architectures for future wireless communication applications. The chapter focuses on the commercial satellite technologies based on the research results presented in [1, 2]. Section 2 provides the comparison results performed by Inmarsat describing the technical characteristics and associated advantages and disadvantages between commercial HTS and typical satellite systems currently available in commercial satellite market. In Section 3, two most commonly satellite network topologies used by existing commercial satellite networks are presented, and the concept of satellite uplink and downlink associated with star satellite network and mesh satellite network is discussed. The satellite network topologies presented lead to Section 4, where four satellite payload architectures are discussed. The legacy analog ABPS payload architecture is shown to be more appropriate for star satellite network than mesh network. Existing digital DBPS and AdDBPS-DCB payload architectures are designed for supporting mesh satellite network with large number of mobile users. Future advanced digital satellite payload architecture, namely AdDBPS-DCB, is also presented in this section. With decoding-demodulating and encoding-modulating processing on-board of the satellite, AR-OBPS allows for packet switching on-board and higher quality of service (QOS) than existing DBPS and AdDBPS-DCB at the expense of higher SWAP-Cost (SWAP-C). Section 4 of the chapter discusses the applications of AdBPS-DCBS and AR-OBPS payloads for supporting 5G users. Four satellite system architecture options are presented for supporting the future 5G users.
The preparation of this chapter was not funded by Gulfstream, and it was done by the author using his own time and resources; thus, it does not represent the Gulfstream’s view on the results presented in this chapter.
The author wishes to thank his wife, Annie Luu-Nguyen, for her immense patience and support.
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Awareness for increased agricultural production is on the increase, arising from the need to feed the ever-increasing human population. Interestingly, almost all agricultural activities generate wastes, which are generated in large quantities in many countries. However, these wastes may constitute a serious threat to human health through environmental pollution and handling them may result in huge economic loss. Unfortunately, in many developing countries where large quantities of these wastes are generated, they are not properly managed because little is known about their potential risks and benefits if properly managed. There are studies that address some of the challenges of agricultural solid wastes as well as suggestions on how they can be properly managed. In this chapter, we intend to explore the major sources of agricultural solid wastes, their potential risks, and how they can be properly managed.",book:{id:"9873",slug:"strategies-of-sustainable-solid-waste-management",title:"Strategies of Sustainable Solid Waste Management",fullTitle:"Strategies of Sustainable Solid Waste Management"},signatures:"Isaac Oluseun Adejumo and Olufemi Adebukola Adebiyi",authors:[{id:"276527",title:"Dr.",name:"Isaac Oluseun",middleName:null,surname:"Adejumo",slug:"isaac-oluseun-adejumo",fullName:"Isaac Oluseun Adejumo"},{id:"328699",title:"Dr.",name:"O.A.",middleName:null,surname:"Adebiyi",slug:"o.a.-adebiyi",fullName:"O.A. Adebiyi"}]},{id:"64270",title:"Decentralization and Solid Waste Management in Urbanizing Ghana: Moving beyond the Status Quo",slug:"decentralization-and-solid-waste-management-in-urbanizing-ghana-moving-beyond-the-status-quo",totalDownloads:2052,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"Waste management is competing with more pressing economic and social issues such as social protection programs, education, and health. The government of Ghana has therefore decentralized the waste management system in the country. With this development, local government authorities and private sector actors are now playing key roles in waste management in the country. This study sought to examine decentralized solid waste management in the Berekum and Dormaa Municipalities in the Brong Ahafo Region of Ghana. Specifically, it analyzed the involvement of the private sector in solid waste management, and the quality of waste management services in the two selected municipalities. Through a survey of 312 households, the study analyzed the performance improvement, regulatory policy, and sustainable service delivery of solid waste management in the municipalities. The study found that there were no mechanisms for full cost recovery to include majority of the residents, who patronize communal collection service. The study therefore recommends the adherence to normative standards and agreed rules, adoption, and use of appropriate cost recovery strategies for low-income groups as well as the restructuring of institutional arrangements to ensure user involvement and enforcement of legislation to improve municipal solid waste management in Ghana.",book:{id:"8580",slug:"municipal-solid-waste-management",title:"Municipal Solid Waste Management",fullTitle:"Municipal Solid Waste Management"},signatures:"Richard Kyere, Michael Addaney and Jonas Ayaribilla Akudugu",authors:[{id:"273978",title:"Ph.D. Student",name:"Michael",middleName:null,surname:"Addaney",slug:"michael-addaney",fullName:"Michael Addaney"},{id:"273981",title:"Mr.",name:"Richard",middleName:null,surname:"Kyere",slug:"richard-kyere",fullName:"Richard Kyere"},{id:"273982",title:"Dr.",name:"Jonas Ayaribilla",middleName:null,surname:"Akudugu",slug:"jonas-ayaribilla-akudugu",fullName:"Jonas Ayaribilla Akudugu"}]},{id:"65314",title:"Municipal Solid Waste Disposal in Mangrove Forest: Environmental Implication and Management Strategies in the Niger Delta, Nigeria",slug:"municipal-solid-waste-disposal-in-mangrove-forest-environmental-implication-and-management-strategie",totalDownloads:1031,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Niger Delta is an oil rich region situated in the southern part of Nigeria. It is made up of nine states which hosts oil industries. There are a handful of businesses (super market, manufacturing companies, etc.) that service the over 40 million people living in the cities. This situation had led to the increase in solid waste in the city. Because of the problem of over population, and poor waste management strategies (e.g., lack of recycling habit and lack of equipment) the mangrove forest had become a dumping ground for waste. This action has impacted the health of aquatic and terrestrial organisms, and has created a public health disaster for citizens because of increase in heavy metal concentration up the food chain. This chapter therefore, identifies poverty, lack of planning, poor behavior and poor technology as key factors affecting effective waste management in the Niger Delta. It suggests that good waste management system can be worked out if there is coordination between research institution and government in the implementation of recommendation by research institutes. Attitudinal change is also necessary on the part of citizens and government to enable a healthy interaction for the purpose of managing waste effectively.",book:{id:"8580",slug:"municipal-solid-waste-management",title:"Municipal Solid Waste Management",fullTitle:"Municipal Solid Waste Management"},signatures:"Aroloye O. Numbere",authors:[{id:"215285",title:"Dr.",name:"Aroloye O.",middleName:null,surname:"Numbere",slug:"aroloye-o.-numbere",fullName:"Aroloye O. 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Nigeria is estimated to have over 178.5 million people and kg/capita/day of 0.26–1.02 MSW, projected to increase with the expansion of the economy which is in need of better articulated MSW management strategies. The enormous natural inland surface and groundwater resources are daily challenged directly and indirectly, through decline in physical, chemical and biological quality. Solid waste disposal along the waterways and leachates from natural activities on materials at dumpsites and landfills was strongly identified and recognized as the source of pollutant inputs. The immediate and projected public health consequences in changes in inland waters were provided for resident aquatic organisms, some of which serves as food for resident human populations that are largely dependent on these water bodies for their daily water requirements.",book:{id:"8580",slug:"municipal-solid-waste-management",title:"Municipal Solid Waste Management",fullTitle:"Municipal Solid Waste Management"},signatures:"Akindayo A. 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment"},{id:"5",title:"Parasitic Infectious Diseases",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Infectious Diseases",id:"6"},selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/343695",hash:"",query:{},params:{id:"343695"},fullPath:"/profiles/343695",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()