<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article  PUBLIC "-//NLM//DTD Journal Publishing DTD v3.0 20080202//EN" "http://dtd.nlm.nih.gov/publishing/3.0/journalpublishing3.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="3.0" xml:lang="en" article-type="research article"><front><journal-meta><journal-id journal-id-type="publisher-id">Health</journal-id><journal-title-group><journal-title>Health</journal-title></journal-title-group><issn pub-type="epub">1949-4998</issn><publisher><publisher-name>Scientific Research Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.4236/health.2021.137059</article-id><article-id pub-id-type="publisher-id">Health-110695</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biomedical&amp;Life Sciences</subject><subject> Medicine&amp;Healthcare</subject></subj-group></article-categories><title-group><article-title>
 
 
  Understanding Human Body Maintenance, Protection, and Modification: Antibodies, Genetics, Stem Cells and Connected Artificial Intelligence Applications—Where Are We?
 
</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Raphael</surname><given-names>R. Ciuman</given-names></name><xref ref-type="aff" rid="aff1"><sub>1</sub></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Mülheim an der Ruhr, Germany</addr-line></aff><pub-date pub-type="epub"><day>12</day><month>07</month><year>2021</year></pub-date><volume>13</volume><issue>07</issue><fpage>766</fpage><lpage>776</lpage><history><date date-type="received"><day>16,</day>	<month>June</month>	<year>2021</year></date><date date-type="rev-recd"><day>18,</day>	<month>July</month>	<year>2021</year>	</date><date date-type="accepted"><day>21,</day>	<month>July</month>	<year>2021</year></date></history><permissions><copyright-statement>&#169; Copyright  2014 by authors and Scientific Research Publishing Inc. </copyright-statement><copyright-year>2014</copyright-year><license><license-p>This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/</license-p></license></permissions><abstract><p>
 
 
  Research in antibody reaction, genetics, stem cells together with advances in imaging techniques and connected referenced-based applications led to a deeper understanding of the physiological mechanisms of functioning and fine regulation of tissue maintenance, protection, and modification in recent years. Meanwhile, the past major research milestones are up to date more than ever. The article comprehensively breaks down these scientific fields in molecular biology, describes the current knowledge, recent advancements and challenges in antibody, genetics, regulation of gene expression respectively, and stem cell research, and gives an overview of the research supporting the areas of artificial intelligence and its connected reference-based applications, which enable the handling of huge genetic and biochemical data amounts.
 
</p></abstract><kwd-group><kwd>Antibody</kwd><kwd> Genetics</kwd><kwd> Imaging</kwd><kwd> Immunology</kwd><kwd> Navigation</kwd><kwd> Artificial Intelligence</kwd><kwd> Stem Cell</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>1. Background</title><p>It has become common knowledge that the molecules providing stability and flexibility for modification of genetic coding are deoxy- and ribonucleic acids (DNA, RNA) [<xref ref-type="bibr" rid="scirp.110695-ref1">1</xref>] and that specific immunity is ensured by alterations of foreign molecule targeting antibodies, molecules consisting of steady and variable regions. Regulation of gene expression is the key mechanism for cell function and tissue development in toti- or pluripotent cells. For example, a cell cannot express epithelial, mesenchymal, and endothelial characteristics at the same time. Organogenesis takes part at certain early time points in body differentiation with ongoing genetic expression regulation together with the possibilities and necessities of epigenetic influences. Consequently, there are mechanisms necessary for fine regulation additionally to the current substrate situation [<xref ref-type="bibr" rid="scirp.110695-ref2">2</xref>] and aerobic state [<xref ref-type="bibr" rid="scirp.110695-ref3">3</xref>] or general growth needs by cell and tissue polarity characteristics [<xref ref-type="bibr" rid="scirp.110695-ref4">4</xref>]. At the same time adult stem cells in the various tissues, adult means the reference to the cell lineage they are originated from, contain the original genetic information. For handling this huge amount of biochemical data computational systems were introduced. And according to the huge amount of genetic data, the underlying mechanisms of physiological modification are numerous as well.</p></sec><sec id="s2"><title>2. Immunology/Antibodies</title><p>Nowadays, the use term “antibody” reflects the finest way of molecule recognition and elimination by the very intra- and interindividual diverse antibody molecules having the responsibility to recognize foreign molecules and protect their molecules. Paul Ehrlich concluded after animal studies that the organism reacts specifically to foreign proteins with the production of matching anti-protein [<xref ref-type="bibr" rid="scirp.110695-ref5">5</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref6">6</xref>]. The discovery of the ABO system by Karl Landsteiner showed that the human immune system recognizes and targets by few major characteristics, whenever the answer of the immune system has to be fast or immediately [<xref ref-type="bibr" rid="scirp.110695-ref7">7</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref8">8</xref>]. Targeting tissue differences and signaling pathways become more complex according to allowed timelines for organic reaction, e.g. slow and fast regenerative tissue or the various epitopes of the Human leukocyte antigen (HLA) system. Polyclonal antibodies make the immunological answer more precise, whereas polyvalent antibodies broaden the immunological answer. Neutralizing antibodies inhibit the molecule action completely, whereas non-neutralizing antibodies inhibit the target molecule only to some degree. Recognizing multiple epitopes, or cross-reactivity respectively can be depending on current tissue characteristics, e.g. pH or state of the tissue. Besides, the human body works with overlapping mechanisms to guarantee functioning, e.g. from various pain signaling cascades to various nerval receptors. Consequently, there is a step from just recognizing and eliminating to tolerating foreign tissue or to steadily accepting and integrating it, e.g. Graft Versus Host Disease (GvHD).</p><p>The reservoir of current existing antibodies represents the preferred design for potential future antibodies in the human body with the generation of a unique antibody variable region. In general, a priming antigen exposure and an exposure in childhood provide a more robust and stable antibody response than a boosting event [<xref ref-type="bibr" rid="scirp.110695-ref9">9</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref10">10</xref>]. Attributable to the fact that slight modifications in one pathway may conserve the concerted properties of the immune system and avoid mesenteric cross-hindrance of proteins and cells. Besides, universal structural elements shorten the time until immunoreactivity [<xref ref-type="bibr" rid="scirp.110695-ref11">11</xref>]. Recombination mechanisms include class switches and somatic hypermutation (maturation of the antibody response) of plasma cells as well as cell differentiation of daughter plasma cells [<xref ref-type="bibr" rid="scirp.110695-ref12">12</xref>]. The latter can be divided into transcriptional and cellular events [<xref ref-type="bibr" rid="scirp.110695-ref13">13</xref>] and can be follicular and extrafollicular located [<xref ref-type="bibr" rid="scirp.110695-ref14">14</xref>]. In addition, the plasticity of the immune system includes conformational heterogeneity and the use of cofactor molecules [<xref ref-type="bibr" rid="scirp.110695-ref15">15</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref16">16</xref>], but always allowing immune cell fate determination by affinity and antibody recall [<xref ref-type="bibr" rid="scirp.110695-ref17">17</xref>]. Not to forget, that cell receptor editing is part of the immune response as well [<xref ref-type="bibr" rid="scirp.110695-ref18">18</xref>]. Antibody folding or conformational organization might define the function of the molecule, although the molecular composition is completely different, e.g. hemoglobin and further molecules for oxygen transport in other species [<xref ref-type="bibr" rid="scirp.110695-ref19">19</xref>]. Besides, molecule folding is rearranged after binding, and flexibility in conformation contributes to a stronger antigen-antibody binding following the molecular function [<xref ref-type="bibr" rid="scirp.110695-ref20">20</xref>].</p><p>Immunity implies lifelong memory and learning processes in the diversity and variability of the antibody repertoire according to intra- and interindividual, respectively species-specific limits. The extent and predetermination of repertoires driven by genetic factors on the one hand or antigen exposure, on the other hand, remain unclear, as well as individual differences in antibody formation [<xref ref-type="bibr" rid="scirp.110695-ref21">21</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref22">22</xref>]. Although, it is clear whenever illness occurs the body pays currently more attention to antigen exposure. Precise prediction of antibody formation within its superstructure due to conformation variability because of e.g. somatic hypermutation remains a challenge. In summary, intraindividual antibody formation reflects the principles of diversity, variability, conformation and timing.</p></sec><sec id="s3"><title>3. Genetics</title><p>All various mechanisms, steady and temporary characteristics and differences of body function are filed in genetics, subsequently regulated by genetic expression and influenced by epigenetics which is by definition inheritable. Regulation extends overall steps in genetic expression, from transcription, over RNA splicing, and transport to translation and posttranslational modification. We are definitely at the beginning of epigenetics and understanding gene expression and epigenetic fine regulation for coding and expression stability in development, survival, and function with already identified examples, like methylation and mutagenesis of methylated bases, chromatin remodeling and histone protein modification, and their importance for RNA editing, genomic imprinting, genomic editing and its crosstalk in the human body [<xref ref-type="bibr" rid="scirp.110695-ref23">23</xref>]. In addition to RNAs responsible for mRNA (messenger RNA) synthesis non-coding RNAs like rRNA (ribosomal RNA), which form together with proteins the two complementary ribosomes, snRNA (small nuclear RNA), which is responsible for transcription splicing mechanisms of pre-mRNA, tRNA (transport RNA), and RNAs like small nucleolar RNAs (snoRNA) which guide chemical modifications of other RNAs, regulate the transcription and translation process to the protein product. Various posttranscriptional RNA modification mechanisms have been studied, e.g. like commonly known polyadenylation at the 3' end [<xref ref-type="bibr" rid="scirp.110695-ref24">24</xref>] and RNA capping on the 5' end [<xref ref-type="bibr" rid="scirp.110695-ref25">25</xref>], determine RNA stability and degradation [<xref ref-type="bibr" rid="scirp.110695-ref26">26</xref>], ensuring a finely balanced protein production.</p><p>The important interaction between epigenetic factors like nutrition, smoking, alcohol consumption, chronic stress, inflammation, microbiota, climate pollution, physical activity and other environmental factors is already well known [<xref ref-type="bibr" rid="scirp.110695-ref27">27</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref28">28</xref>]. Genetics overcomes the time limits of, e.g. immunology and antibody reaction by constant integrating procedures, with every processing and cell division having a necessary time of memory. In addition to identifying the adequate target, challenges of genetic research consist in recognizing the underlying details in the techniques for genetic transcription and translation. Expression stimulation is characterized by the quantity and duration of gene expression regulation. The functionality can either be genetically controlled or by controlling the gene product itself.</p><p>The importance of noncoding RNA for regulation is underlined by its various forms. Mechanisms for co- and posttranslational genetic modifications include RNA interference by microRNA (miRNAs), small interfering RNAs (siRNAs), long non-coding RNA or non-coding circular RNA, that alternate quantity of gene expression [<xref ref-type="bibr" rid="scirp.110695-ref29">29</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref30">30</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref31">31</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref32">32</xref>]. It seems that the barriers between DNA repair and modification mechanisms are fluent, just reflecting the general structural principles [<xref ref-type="bibr" rid="scirp.110695-ref33">33</xref>]. Transposons are genetic elements that can relocate between DNA or RNA genomic sites using a “cut and paste” mechanism or a “copy and paste” mechanism to achieve a high replication or transcription rate [<xref ref-type="bibr" rid="scirp.110695-ref34">34</xref>]. In addition, the term retrograde signaling does not only include the impact that proteins and various nucleic acids have on translation and genomics but includes communication of cell organelles as well. The extent and limits of retrograde signaling are an interesting topic of current research. It seems to have important implications, in epigenetics as well and for cell survival in young and old age, e.g., in communication between mitochondrion and cell nucleus and regulation of radical oxygen species (ROS), chromatin and histone formation, and for adjustments in metabolic and stress responses [<xref ref-type="bibr" rid="scirp.110695-ref35">35</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref36">36</xref>]. In contrast, the term anterograde signaling is used for nuclear-encoded factors.</p></sec><sec id="s4"><title>4. Stem Cells</title><p>Regeneration with the need for perfect alignment as a precondition for function characterizes the capability of stem cells. Regeneration of blood and immune function by hematopoietic stem cells, which consist of a surprisingly heterogeneous population of multipotent stem cells which collectively possess the potential to form all blood cell types, has lead the way to discoveries and understanding of the gradual differences in the regeneration of organic function in the human body [<xref ref-type="bibr" rid="scirp.110695-ref37">37</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref38">38</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref39">39</xref>]. Autologous hematologic stem cells like megakaryocytes or platelets respectively are becoming the first cells overcoming the hurdles of laboratory reproduction in feeder cell-free settings [<xref ref-type="bibr" rid="scirp.110695-ref40">40</xref>]. For recapitulation, stem cells are by definition undifferentiated cells and totipotent or pluripotent. Adult stem cells are multipotent, meaning they refer to the cell lineage they are originated from. In contrast, progenitor cells cannot divide indefinitely, and precursor cells differentiate into one specific cell type. Induced pluripotent stem cells are converted mature body cells.</p><p>Stem cells can replicate by all possible types of cell division, either symmetric, intrinsic asymmetrical division, and extrinsic asymmetrical division. The latter depends on the signaling of the surrounding cells. Equal for all stem cell-stimulating pathways, either for induced pluripotent stem cells [<xref ref-type="bibr" rid="scirp.110695-ref41">41</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref42">42</xref>], or resident stem cells, by nonmitotic cell transdifferentiation, the mitotic proliferation of a subset of cells or differentiation of resident stem cells, either of epithelial origin (derived from the oral mucosa, amniotic membrane, epidermis, hair follicle), mesenchymal origin (bone marrow, adipose-derived, amniotic membrane, placenta, umbilical cord), neural crest origin (dental pulp stem cells) or by introducing of exogenous pluripotent precursors, e.g. human fibroblasts or adipocytes, is that the challenges consist in controlled cell growth with fully functional and organized cells, variable human response to resorption, recellularization, regeneration, and potentially disastrous consequences, e.g., tissue transformation [<xref ref-type="bibr" rid="scirp.110695-ref43">43</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref44">44</xref>].</p><p>Cell or tissue growth and regeneration are always under the control and fine regulation by intracellular, regional, and distant molecules, namely, cytokines, growth factors, or hormones. Regulation is either performed by direct molecule stimulation or by indirect molecule modification before allowing the target molecule its action to unfold. Regulation of intra- or extracellular receptors in quantity or quality, molecule modification respectively, is the precondition before action is allowed to unfold on the genetic level. In contrast to cytokines, which can represent growth factors as well, growth factors have always stimulating properties [<xref ref-type="bibr" rid="scirp.110695-ref45">45</xref>]. Besides, cell communication, often summarized with non-autonomous regulation, with its various molecules, e.g., growth hormones or via neurons with retrograde neuronal signaling up to brain structures like the hypothalamus and for example, the subsequent metabolic rearrangements in mitochondria, has a crucial role for environment adjustments and aging [<xref ref-type="bibr" rid="scirp.110695-ref35">35</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref46">46</xref>].</p></sec><sec id="s5"><title>5. Connected Artificial Intelligence Applications</title><p>Acquired data quantities connected with reference-based individualized applications, e.g., in antibody designing, genetics, radiology, navigation, [<xref ref-type="bibr" rid="scirp.110695-ref47">47</xref>] [<xref ref-type="bibr" rid="scirp.110695-ref48">48</xref>], and general reference-based applications in all kinds of analytics and science have become ubiquitous (<xref ref-type="table" rid="table1">Table 1</xref>). The more precise the target or reference data the more successful the match. Consequently, database design, development, and long-term management of specific databases and database collections are crucial. Fast item identification and comparison, data extraction, as well as calculation algorithms in acquired data amounts are the domains of these applications. Further, the applied algorithms help to analyze large databases, either by logic,</p><table-wrap id="table1" ><label><xref ref-type="table" rid="table1">Table 1</xref></label><caption><title> Glossary of the scientific fields for general and individualized artificial intelligence applications</title></caption><table><tbody><thead><tr><th align="center" valign="middle" >Scientific field</th><th align="center" valign="middle" >Definition</th></tr></thead><tr><td align="center" valign="middle" >artificial intelligence</td><td align="center" valign="middle" >general term as summarization for all computational benefits based on data gathering, collection and analysis</td></tr><tr><td align="center" valign="middle" >bioinformatics</td><td align="center" valign="middle" >general term for data gathering, collection and analysis in biology with its subdivisions genomics, proteomics, etc., synonymous use with computational biology</td></tr><tr><td align="center" valign="middle" >computational biology</td><td align="center" valign="middle" >general term for data collection and analysis in biology with its subdivisions genomics, proteomics, etc., synonymous use with bioinformatics</td></tr><tr><td align="center" valign="middle" >cloud technology</td><td align="center" valign="middle" >superimposed computational organization for data resources, extraction and interchange limited to a single organization or available to multiple organizations (public could) previously to peripheral server and customer usage; composed of its subdivisions computing, network, identity, storage, database, content, communication, collaboration, monitoring, queue organization, financial resources</td></tr><tr><td align="center" valign="middle" >computer assisted medicine</td><td align="center" valign="middle" >computational assistance and its applications for calculation, decision making and signaling in medicine</td></tr><tr><td align="center" valign="middle" >cybernetics</td><td align="center" valign="middle" >organization of regulation and information transfer their structures, constraints and possibilities in systems, e.g. biology, computation, etc.</td></tr><tr><td align="center" valign="middle" >data analysis</td><td align="center" valign="middle" >logic: conclusional analytics according to predefined algorithms and margins mathematical optimization: algorithms to overcome data gaps and selection of the best choice based on classification, correlation, regression, probability analysis or reference data network analysis: organization and analysis of item relations, interactions, sequences and consequences statistics: mathematical algorithms for data collection, summarization and extraction probability analysis: mathematical algorithms after executed statistical or network analysis for decision making</td></tr><tr><td align="center" valign="middle" >database organization</td><td align="center" valign="middle" >data organized for extraction and presentation in specific or superimposed database collections, synonymous use with data mining</td></tr><tr><td align="center" valign="middle" >deep learning</td><td align="center" valign="middle" >algorithms for self-modification based on predefined principles; term mostly used for complicated network settings, synonymous use with representation learning</td></tr><tr><td align="center" valign="middle" >genomics</td><td align="center" valign="middle" >sequencing and analysing of the complete genetic material and its structure, function, mapping and evolution of one individuum or species</td></tr><tr><td align="center" valign="middle" >genetics</td><td align="center" valign="middle" >analysis of the characteristics of the specific genes in one individuum or species</td></tr><tr><td align="center" valign="middle" >internet of things</td><td align="center" valign="middle" >superimposed computational organization for data extraction and interchange on the internet</td></tr><tr><td align="center" valign="middle" >machine learning</td><td align="center" valign="middle" >predefined algorithms criteria for data analysis and algorithm modification to optimize its function, e.g. feature detection, classification and usage in feature or representation learning</td></tr><tr><td align="center" valign="middle" >mechatronics</td><td align="center" valign="middle" >general term for interdisciplinary engineering of controlled mechanical devices for human assistance with its subdivisions computer, electronics, robotics, telecommunications, synonymous use with automation, electromechanical engineering, robotics</td></tr><tr><td align="center" valign="middle" >navigation</td><td align="center" valign="middle" >assisting applications for feedback and signaling of the current or predefined location</td></tr><tr><td align="center" valign="middle" >proteomics</td><td align="center" valign="middle" >one field of bioinformatics analysing the composition, structure, function, interaction and evolution of proteins</td></tr><tr><td align="center" valign="middle" >radionics</td><td align="center" valign="middle" >data collection, analysis, presentation and assisting decision making systems in radiology</td></tr><tr><td align="center" valign="middle" >robotics</td><td align="center" valign="middle" >general term for interdisciplinary engineering of controlled mechanical devices for human assistance with its subdivisions, computer, electronics, mechanics, telecommunications, synonymous use with automation, electromechanical engineering, mechatronics</td></tr></tbody></table></table-wrap><p>artificial neural networks, statistics, probability analysis, or mathematical optimization, with or without machine learning.</p><p>Different steps of data analysis might be distinguished, like data acquisition, the definition of target, data (pre) processing like reconstruction and denoising, feature extraction, selection of the relevant features, classification, and interpretation [<xref ref-type="bibr" rid="scirp.110695-ref49">49</xref>]. The validity, reliability, effectiveness, and applicability of the applications have to be clarified for the specific setting [<xref ref-type="bibr" rid="scirp.110695-ref50">50</xref>]. Every step of analysis might be subject to great variability. Therefore, responsible, comprehensible handling of the submitted data and applied analysis methods is an indispensable requirement [<xref ref-type="bibr" rid="scirp.110695-ref51">51</xref>], what will lead to an increased usage of artificial intelligence due to the needs for fast idem identification and comparison, data extraction and calculation in growing data sets in the future. Besides, the value of assisting systems consists in the higher achievable resolutions of the acquired data compared with the human senses, like visuality or haptic perception.</p></sec><sec id="s6"><title>6. Conclusion</title><p>Research in antibody reaction, genetics, and stem cells opened the understanding of the resources and mechanisms of human body maintenance, protection, and modification, based on and in continuation with the major discoveries of the past. The handling of huge genetic and biochemical data amounts, particularly in the regulation of gene expression and antibody recombination mechanisms, is supported by the various areas of artificial intelligence.</p></sec><sec id="s7"><title>Funding</title><p>The author has no funding to announce.</p></sec><sec id="s8"><title>Conflicts of Interest</title><p>The author has no relevant financial or non-financial interests to disclose. The author has no conflicts of interest to declare that are relevant to the content of this article. The author certifies that he has no affiliations with or involvement in any organizations or entity with a financial interest in the subject or materials discussed in this manuscript. The author has no financial or proprietary interest in any material discussed in this article.</p></sec><sec id="s9"><title>Cite this paper</title><p>Ciuman, R.R. (2021) Understanding Human Body Maintenance, Protection, and Modification: Antibodies, Genetics, Stem Cells and Connected Artificial Intelligence Applications—Where Are We?. Health, 13, 766-776. https://doi.org/10.4236/health.2021.137059</p></sec></body><back><ref-list><title>References</title><ref id="scirp.110695-ref1"><label>1</label><mixed-citation publication-type="other" xlink:type="simple">Watson, J.D. and Crick, F.H. (1953) Molecular Structure of Nucleic Acids; a Structure for Deoxyribose Nucleic Acid. Nature, 171, 737-738.  
https://doi.org/10.1038/171737a0</mixed-citation></ref><ref id="scirp.110695-ref2"><label>2</label><mixed-citation publication-type="other" xlink:type="simple">Gaal, T., Bartlett, M.S., Ross, W., Turnbough, C.L. and Gourse, R.L. (1997) Transcription Regulation by Initiating NTP Concentration: rRNA Synthesis in Bacteria. Science, 278, 2092-2097. https://doi.org/10.1126/science.278.5346.2092</mixed-citation></ref><ref id="scirp.110695-ref3"><label>3</label><mixed-citation publication-type="other" xlink:type="simple">Trauner, A., Lougheed, K.E.A., Bennett, M.H., Hingley-Wilson, S.M. and Williams, H.D. (2012) The Dormancy Regulator DosR Controls Ribosome Stability in Hypoxic Mycobacteria. Journal of Biological Chemistry, 287, 24053-24063.  
https://doi.org/10.1074/jbc.M112.364851</mixed-citation></ref><ref id="scirp.110695-ref4"><label>4</label><mixed-citation publication-type="other" xlink:type="simple">Jülicher, F. and Eaton, S. (2017) Emergence of Tissue Shape Changes from Collective Cell Behaviours. Seminars in Cell and Developmental Biology, 67, 103-112.  
https://doi.org/10.1016/j.semcdb.2017.04.004</mixed-citation></ref><ref id="scirp.110695-ref5"><label>5</label><mixed-citation publication-type="other" xlink:type="simple">Ehrlich, P. (1891) Experimental Studies on Immunity I (Translation). Experimentelle Untersuchungen über Immunitat. I. Deutsche Medizinische Wochenschrift, 17, 976-979. (In German) https://www.pei.de  
https://doi.org/10.1055/s-0029-1206682</mixed-citation></ref><ref id="scirp.110695-ref6"><label>6</label><mixed-citation publication-type="other" xlink:type="simple">Ehrlich, P. (1891) Experimental Studies on Immunity II (Translation). Experimetelle Untersuchungen über Immunitat. Deutsche Medizinische Wochenschrift, 17, 1218-1219. (In German) https://www.pei.de 
https://doi.org/10.1055/s-0029-1206825</mixed-citation></ref><ref id="scirp.110695-ref7"><label>7</label><mixed-citation publication-type="other" xlink:type="simple">Landsteiner, K. (1900) To the Knowledge of Antifermentative, Lytic and Agglutinatic Effects of the Blood Serum and the Lymphatic Fluid. Zur Kenntnis der antifermentativen, lytischen und agglutinierenden Wirkungen des Blutserums und der Lymphe. Zentralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, 27, 357-362. (In German)  
https://archive.org/details/bub_gb_NAsuAAAAIAAJ/page/n369/mode/2up</mixed-citation></ref><ref id="scirp.110695-ref8"><label>8</label><mixed-citation publication-type="other" xlink:type="simple">Landsteiner, K. (1901) On Agglutination Manifestations of Normal Human Blood. über Agglutinationserscheinungen normalen menschlichen Blutes. Wiener Klinische Wochenschrift, 14, 1132-1134. (In German)  
https://www.billrothhaus.at/index.php?option=com_content&amp;id=68&amp;task=view&amp;Itemid=86</mixed-citation></ref><ref id="scirp.110695-ref9"><label>9</label><mixed-citation publication-type="other" xlink:type="simple">Francis, T. (1960) On the Doctrine of Original Antigenic Sin. Proceedings of the American Philosophical Society, 104, 572-578. https://www.jstor.org/stable/985534</mixed-citation></ref><ref id="scirp.110695-ref10"><label>10</label><mixed-citation publication-type="other" xlink:type="simple">Yewdell, W.J. and Santos, J.J.S. (2021) Original Antigenic Sin: How Original? How Sinful? Cold Spring Harbor Perspectives in Medicine, 11, a038786.  
https://doi.org/10.1101/cshperspect.a038786</mixed-citation></ref><ref id="scirp.110695-ref11"><label>11</label><mixed-citation publication-type="other" xlink:type="simple">Gilchuk, I., Gilchuk, P., Sapparapu, G., Lampley, R., Singh, V., Kose, N., Blum, D.L., Hughes, L.J., Satheskumar, P.S., Townsend, M.B., Kondas, A.V., Reed, Z., Weiner, Z., Olson, V., Hammarlund, E., Raue, H.P., Slifka, M.K., Slaughter, J.C., Graham, B.S., Edwards, K.M., Eisenberg, R.J., Cohen, G.H., Joyce, S. and Crowe, J.E. (2016) Cross-Neutralizing and Protective Human Antibody Specifities to Poxvirus Infection. Cell, 167, 684-694. https://doi.org/10.1016/j.cell.2016.09.049</mixed-citation></ref><ref id="scirp.110695-ref12"><label>12</label><mixed-citation publication-type="other" xlink:type="simple">Chi, X., Li, Y. and Qiu, X. (2020) V(D)J Recombination, Somatic Hypermutation and Class Switch Recombination of Immunoglobulins and Regulation. Immunology, 160, 233-247. https://doi.org/10.1111/imm.13176</mixed-citation></ref><ref id="scirp.110695-ref13"><label>13</label><mixed-citation publication-type="other" xlink:type="simple">Nutt, S.L., Taubenheim, N., Hasbold, J., Corcoran, L. and Hodgkin, P.D. (2011) The Genetic Network Controlling Plasma Cell Differentiation. Seminars in Immunology, 23, 341-349. https://doi.org/10.1016/j.smim.2011.08.010</mixed-citation></ref><ref id="scirp.110695-ref14"><label>14</label><mixed-citation publication-type="other" xlink:type="simple">Totonchy, J. (2017) Extrafollicular Activities: Perspectives on HIV Infection, Germinal Center-Independent Maturation, and KSHV-Mediated Lymphoproliferation. Current Opinion in Virology, 26, 69-73.  
https://doi.org/10.1016/j.coviro.2017.07.016</mixed-citation></ref><ref id="scirp.110695-ref15"><label>15</label><mixed-citation publication-type="other" xlink:type="simple">Kenter, A.L. and Feeney, A.J. (2019) New Insights Emerge as Antibody Repertoire Diversification Meets Chromosome Conformation. F1000Research, 8, 347.  
https://doi.org/10.12688/f1000research.17358.1</mixed-citation></ref><ref id="scirp.110695-ref16"><label>16</label><mixed-citation publication-type="other" xlink:type="simple">Kanyavuz, A., Marey-Jarossay, A., Lacroix-Desmazes, S. and Dimitrov, J.A. (2019) Breaking the Law: Unconventional Strategies for Antibody Diversification. Nature Reviews Immunology, 19, 355-368. https://doi.org/10.1038/s41577-019-0126-7</mixed-citation></ref><ref id="scirp.110695-ref17"><label>17</label><mixed-citation publication-type="other" xlink:type="simple">Higgins, B.W., McHeyzer-Williams, L.J. and McHeyzer-Williams, M.G. (2019) Programming Isotype-Specific Plasma Cell Function. Trends in Immunology, 40, 345-357. https://doi.org/10.1016/j.it.2019.01.012</mixed-citation></ref><ref id="scirp.110695-ref18"><label>18</label><mixed-citation publication-type="other" xlink:type="simple">Nemazee, D. (2017) Mechanisms of Central Tolerance for B Cells. Nature Reviews Immunology, 17, 281-294. https://doi.org/10.1038/nri.2017.19</mixed-citation></ref><ref id="scirp.110695-ref19"><label>19</label><mixed-citation publication-type="other" xlink:type="simple">Hoy, J.A., Robinson, H., Trent, J.T., Kakar, S., Smagghe, B.J. and Hargrove, M.S. (2007) Plant Hemoglobins: A Molecular Fossil Record for the Evolution of Oxygen Transport. Journal of Molecular Biology, 371, 168-179.  
https://doi.org/10.1016/j.jmb.2007.05.029</mixed-citation></ref><ref id="scirp.110695-ref20"><label>20</label><mixed-citation publication-type="other" xlink:type="simple">Wilson, I.A. and Stanfield, R.L. (2021) 50 Years of Structural Immunology. Journal of Biological Chemistry, 296, Article ID: 100745.  
https://doi.org/10.1016/j.jbc.2021.100745</mixed-citation></ref><ref id="scirp.110695-ref21"><label>21</label><mixed-citation publication-type="other" xlink:type="simple">Imkeller, K. and Wardemann, H. (2018) Assessing Human B Cell Repertoire Diversity and Convergence. Immunological Reviews, 284, 51-66.  
https://doi.org/10.1111/imr.12670</mixed-citation></ref><ref id="scirp.110695-ref22"><label>22</label><mixed-citation publication-type="other" xlink:type="simple">Greiff, V., Menzel, U., Miho, E., Weber, C., Riedel, R., Cook, S., Valai, A., Lopes, T., Radbruch, A., Winkler, T.H. and Reddy, S.T. (2017) Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development. Cell Reports, 19, 1467-1478.  
https://doi.org/10.1016/j.celrep.2017.04.054</mixed-citation></ref><ref id="scirp.110695-ref23"><label>23</label><mixed-citation publication-type="other" xlink:type="simple">Friedman, L.M. and Avraham, K.B. (2009) MicroRNAs and Epigenetic Regulation in the Mammalian Inner Ear: Implications for Deafness. Mammalian Genome, 20, 581-603. https://doi.org/10.1007/s00335-009-9230-5</mixed-citation></ref><ref id="scirp.110695-ref24"><label>24</label><mixed-citation publication-type="other" xlink:type="simple">Ogorodnikov, A., Kargapolova, Y. and Dankcwardt, S. (2016) Processing and Transcriptome Expansion at the mRNA 3’ End in Health and Disease: Finding the Right End. Pflügers Archiv, 468, 993-1012. https://doi.org/10.1007/s00424-016-1828-3</mixed-citation></ref><ref id="scirp.110695-ref25"><label>25</label><mixed-citation publication-type="other" xlink:type="simple">Ramanathan, A., Robb, G.B. and Chan, S.H. (2016) MRNA Capping: Biological Functions and Applications. Nucleic Acids Research, 44, 7511-7526.  
https://doi.org/10.1093/nar/gkw551</mixed-citation></ref><ref id="scirp.110695-ref26"><label>26</label><mixed-citation publication-type="other" xlink:type="simple">Bachellerie, J.P., Cavaillé, J. and Hüttenhofer, A. (2002) The Expanding snoRNA World. Biochimie, 84, 775-790. https://doi.org/10.1016/S0300-9084(02)01402-5</mixed-citation></ref><ref id="scirp.110695-ref27"><label>27</label><mixed-citation publication-type="other" xlink:type="simple">Hou, H.M. and Zhao, H.Y. (2021) Epigenetic Factors in Atherosclerosis: DNA Methylation, Folic Acid Metabolism, and Intestinal Microbiota. Clinica Chimica Acta, 512, 7-11. https://doi.org/10.1016/j.cca.2020.11.013</mixed-citation></ref><ref id="scirp.110695-ref28"><label>28</label><mixed-citation publication-type="other" xlink:type="simple">Ramos-Lopez, O., Milagro, F.I., Riezu-Boj, J.I. and Martinez, J.A. (2021) Epigenetic Signatures Underlying Inflammation: An Interplay of Nutrition, Physical Activity, Metabolic Diseases, and Environmental Factors for Personalized Nutrition. Inflammation Research, 70, 29-49. https://doi.org/10.1007/s00011-020-01425-y</mixed-citation></ref><ref id="scirp.110695-ref29"><label>29</label><mixed-citation publication-type="other" xlink:type="simple">Pasquier, C. and Robichon, A. (2020) Computational Prediction of miRNA/mRNA Duplexomes at the Whole Human Genome Scale Reveals Functional Subnetworks of Interacting Genes with Embedded miRNA Annealing Motifs. Computational Biology and Chemistry, 88, Article ID: 107366.  
https://doi.org/10.1016/j.compbiolchem.2020.107366</mixed-citation></ref><ref id="scirp.110695-ref30"><label>30</label><mixed-citation publication-type="other" xlink:type="simple">Wells, A., Pobezinskaya, E.L. and Pobezinsky, L.A. (2020) Non-Coding RNAs in CD8 T Cell Biology. Molecular Immunology, 120, 67-73.  
https://doi.org/10.1016/j.molimm.2020.01.023</mixed-citation></ref><ref id="scirp.110695-ref31"><label>31</label><mixed-citation publication-type="other" xlink:type="simple">Gutbrod, M.J. and Martienssen, R.A. (2020) Conserved Chromosomal Functions of RNA Interference. Nature Reviews Genetics, 21, 311-331.  
https://doi.org/10.1038/s41576-019-0203-6</mixed-citation></ref><ref id="scirp.110695-ref32"><label>32</label><mixed-citation publication-type="other" xlink:type="simple">Zhou, M., Xiao, M.-S., Li, Z. and Huang, C. (2020) New Progresses of Circular RNA Biology: From Nuclear Export to Degradation. RNA Biology, 1-9.  
https://doi.org/10.1080/15476286.2020.1853977</mixed-citation></ref><ref id="scirp.110695-ref33"><label>33</label><mixed-citation publication-type="other" xlink:type="simple">Durandy, A. and Kracker, S. (2012) Immunoglobulin Class-Switch Recombination Deficiencies. Arthritis Research &amp; Therapy, 14, 218. https://doi.org/10.1186/ar3904</mixed-citation></ref><ref id="scirp.110695-ref34"><label>34</label><mixed-citation publication-type="other" xlink:type="simple">Kim, A. and Pykko, I. (2011) Size Matters, Versatile Use of Piggy Bac Transposons as a Genetic Manipulation Tool. Molecular and Cellular Biochemistry, 354, 301-309.  
https://doi.org/10.1007/s11010-011-0832-3</mixed-citation></ref><ref id="scirp.110695-ref35"><label>35</label><mixed-citation publication-type="other" xlink:type="simple">Miller, H.A., Dean, S.E., Pletcher, S.D. and Leiser, S.F. (2020) Cell Non-Autonomous Regulation of Health and Longevity. eLife, 9, e62659.  
https://doi.org/10.7554/eLife.62659</mixed-citation></ref><ref id="scirp.110695-ref36"><label>36</label><mixed-citation publication-type="other" xlink:type="simple">Vizioli, M.G., Liu, T., Miller, K.N., Robertson, N.A., Gilroy, K., Lagnado, A.B., Garcia, A.P., Kiourtis, C., Dasgupta, N., Lei, X., Kruger, P.J., Nixon, C., Clark, W., Jurk, D., Bird, T.G., Passos, J.F., Berger, S.L., Dou, Z. and Adams, P.D. (2020) Mitochondria-to-Nucleus Retrograde Signaling Drives Formation of Cytoplasmic Chromatin and Inflammation in Senescence. Genes &amp; Development, 34, 428-445.  
https://doi.org/10.1101/gad.331272.119</mixed-citation></ref><ref id="scirp.110695-ref37"><label>37</label><mixed-citation publication-type="other" xlink:type="simple">Thomas, E.D., Lochte, H.L., Lu, W.C. and Ferrebee, J.W. (1957) Intravenous Infusion of Bone Marrow in Patients Receiving Radiation and Chemotherapy. The New England Journal of Medicine, 257, 491-496.  
https://doi.org/10.1056/NEJM195709122571102</mixed-citation></ref><ref id="scirp.110695-ref38"><label>38</label><mixed-citation publication-type="other" xlink:type="simple">Müller-Sieburg, C.E., Cho, R.H., Thoman, M., Adkins, B. and Sieburg, H.B. (2002) Deterministic Regulation of Hematopoeitic Stem Cell Self-Renewal and Differentiation. Blood, 100, 1302-1309.  
https://doi.org/10.1182/blood.V100.4.1302.h81602001302_1302_1309</mixed-citation></ref><ref id="scirp.110695-ref39"><label>39</label><mixed-citation publication-type="other" xlink:type="simple">Gupta, P.K. and Saxena, A. (2021) HIV/AIDS: Current Updates on the Disease, Treatment and Prevention. The Proceedings of the National Academy of Sciences, India, Section B: Biological Sciences, 1-16. (Online Ahead of Print)  
https://doi.org/10.1007/s40011-021-01237-y</mixed-citation></ref><ref id="scirp.110695-ref40"><label>40</label><mixed-citation publication-type="other" xlink:type="simple">Nakamura, S., Sugimoto, N. and Eto, K. (2020) Ex Vivo Generation of Platelet Products from Human iPs Cells. Inflammation and Regeneration, 40, 30.  
https://doi.org/10.1186/s41232-020-00139-2</mixed-citation></ref><ref id="scirp.110695-ref41"><label>41</label><mixed-citation publication-type="other" xlink:type="simple">Gurdon, J.B. (1962) The Development Capacity of Nuclei Taken from Intestinal Epithelium Cells of Feeding Tadpoles. Journal of Embryology and Experimental Morphology, 10, 622-640. http://dev.biologists.org/content/develop/10/4/622.full.pd  
https://doi.org/10.1242/dev.10.4.622</mixed-citation></ref><ref id="scirp.110695-ref42"><label>42</label><mixed-citation publication-type="other" xlink:type="simple">Takahashi, K. and Yamanaka, S. (2006) Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126, 663-676. https://doi.org/10.1016/j.cell.2006.07.024</mixed-citation></ref><ref id="scirp.110695-ref43"><label>43</label><mixed-citation publication-type="other" xlink:type="simple">Zuliani, G.F. (2012) Stem Cell Based Regenerative Medicine: What Is Fiction? And What Is Science Fiction? Journal of Otology &amp; Rhinology, 1.</mixed-citation></ref><ref id="scirp.110695-ref44"><label>44</label><mixed-citation publication-type="other" xlink:type="simple">Ciuman, R.R. (2013) Inner Ear Symptoms and Disease: Pathophysiological Understanding and Therapeutic Options. Medical Science Monitor, 19, 1195-1210.  
https://doi.org/10.12659/MSM.889815</mixed-citation></ref><ref id="scirp.110695-ref45"><label>45</label><mixed-citation publication-type="other" xlink:type="simple">Levi-Montalcini, R., Dal Toso, R., della Valle, F., Skaper, S.D. and Leon, A. (1995) Update of the NGF Saga. Journal of the Neurological Sciences, 130, 119-127.  
https://doi.org/10.1016/0022-510X(95)00007-O</mixed-citation></ref><ref id="scirp.110695-ref46"><label>46</label><mixed-citation publication-type="other" xlink:type="simple">Zhang, Y., Lanjuin, A., Chowdhury, S.R., Mistry, M., Silvy-Garcia, C.G., Weir, H.J., Lee, C.L., Escoubas, C.C., Tabakoviy, E. and Mair, W.B. (2019) Neuronal TORC1 Modulates Longevity via AMPK and Cell Nonautomatous Regulation of Mitochondrial Dynamics in C. elegans. eLife, 8, e49158. https://doi.org/10.7554/eLife.49158</mixed-citation></ref><ref id="scirp.110695-ref47"><label>47</label><mixed-citation publication-type="other" xlink:type="simple">Gampala, S., Vankeshwaram, V. and Gadula, S.S.P. (2020) Is Artificial Intelligence the New Friend for Radiologists? A Review Article. Cureus, 12, e11137.  
https://doi.org/10.7759/cureus.11137</mixed-citation></ref><ref id="scirp.110695-ref48"><label>48</label><mixed-citation publication-type="other" xlink:type="simple">Frankish, A., Diekhans, M., Jungreis, I., Lagarde, J., Loveland, J.E., Mudge, J.M., Sisu, C., Wright, J.C., Armstrong, J., Barnes, I., Berry, A., Bifnell, A., Boix, C., Carbonell Sala, S., Cunningham, F., Di Domenico, T., Donaldson, S., Fiddes, I.T., Garcia Giron, C., Gonzalez, J.M., Grego, T., Hardy, M., Hourlier, T., Howe, K.L., Hunt, T., Izuogu, O.G., Johnson, R., Martin, F.J., Martinez, L., Mohanan, S., Muir, P., Navarro, F.C.P., Parker, A., Pei, B., Pozo, F., Riera, F.C., Ruffier, M., Schmitt, B.M., Stapleton, E., Suner, M.M., Sycheva, I., Uszczynska-Rarajczak, B., Wolf, M.Y., Xu, J., Yang, Y.T., Yates, A., Zerbino, D., Zhang, Y., Choudhary, J.S., Gerstein, M., Guigo, R., Hubbard, T.J.P., Kellis, M., Paten, B., Tress, M.L. and Flicek, P. (2021) Gencode 21. Nucleic Acids Research, 49, D916-D923. https://doi.org/10.1093/nar/gkaa1087</mixed-citation></ref><ref id="scirp.110695-ref49"><label>49</label><mixed-citation publication-type="other" xlink:type="simple">Willemink, M.J., Varga-Szemes, A., Schoepf, U., Codari, M., Nieman, K., Fleischmann, D. and Mastrodicasa, D. (2021) Emerging Methods for the Characterization of Ischemic Heart Disease: Ultrafasr Doppler Angiography, Micro-CT, Photon-Counting CT, Novel MRI and PET Techniques, and Artificial Intelligence. European Radiology Experimental, 5, 12. https://doi.org/10.1186/s41747-021-00207-3</mixed-citation></ref><ref id="scirp.110695-ref50"><label>50</label><mixed-citation publication-type="other" xlink:type="simple">Kocak, B., Kus, E.A. and Kilickesmez, O. (2021) How to Read and Review Papers on Machine Learning and Artificial Intelligence in Radiology: A Survival Guide to Key Methodological Concepts. European Radiology, 31, 1819-1830.  
https://doi.org/10.1007/s00330-020-07324-4</mixed-citation></ref><ref id="scirp.110695-ref51"><label>51</label><mixed-citation publication-type="other" xlink:type="simple">Attenberger, U.I. and Langs, G. (2021) How Does Radiomics Actually Work? Rofo, 193, 652-657. https://doi.org/10.1055/a-1293-8953</mixed-citation></ref></ref-list></back></article>