{"title":"Host Manipulation Mechanisms of SARS-CoV-2","authors":"Steven E. Massey","doi":"10.1007/s10441-021-09425-z","DOIUrl":"10.1007/s10441-021-09425-z","url":null,"abstract":"<div><p>Viruses are the simplest of pathogens, but possess sophisticated molecular mechanisms to manipulate host behavior, frequently utilizing molecular mimicry. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to bind to the host receptor neuropilin-1 in order to gain entry into the cell. To do this, the virus utilizes its spike protein polybasic cleavage site (PCS), which mimics the CendR motif of neuropilin-1’s endogenous ligands. In addition to facilitating cell entry, binding to neuropilin-1 has analgesic effects. We discuss the potential impact of neuropilin-1 binding by SARS-CoV-2 in ameliorating sickness behavior of the host, and identify a convergent evolutionary strategy of PCS cleavage and subsequent neuropilin binding in other human viruses. In addition, we discuss the evolutionary leap of the ancestor of SARS-COV-2, which involved acquisition of the PCS thus faciliting binding to the neuropilin-1 receptor. Acquisition of the PCS by the ancestor of SARS-CoV-2 appears to have led to pleiotropic beneficial effects including enhancement of cell entry via binding to ACE2, facilitation of cell entry via binding to neuropilin-1, promotion of analgesia, and potentially the formation of decoy epitopes via enhanced shedding of the S1 subunit. Lastly, other potential neuromanipulation strategies employed by SARS-CoV-2 are discussed, including interferon suppression and the resulting reduction in sickness behavior, enhanced transmission through neurally mediated cough induction, and reduction in sense of smell.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"70 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2021-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10441-021-09425-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39722149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Concept of Evenness/Unevenness: Less Evenness or More Unevenness?","authors":"Hans-Rolf Gregorius, Elizabeth M. Gillet","doi":"10.1007/s10441-021-09429-9","DOIUrl":"10.1007/s10441-021-09429-9","url":null,"abstract":"<div><p>While evenness is understood to be maximal if all types (species, genotypes, alleles, etc.) are represented equally (via abundance, biomass, area, etc.), its opposite, maximal unevenness, either remains conceptually in the dark or is conceived as the type distribution that minimizes the applied evenness index. The latter approach, however, frequently leads to <i>conceptual inconsistency</i> due to the fact that the minimizing distribution is not specifiable or is monomorphic. The state of monomorphism, however, is indeterminate in terms of its evenness/unevenness characteristics. Indeed, the semantic indeterminacy also shows up in the observation that monomorphism represents a state of pronounced discontinuity for the established evenness indices. This serious conceptual inconsistency is latent in the widely held idea that evenness is an independent component of diversity. As a consequence, the established evenness indices largely appear as indicators of relative polymorphism rather than as indicators of evenness. In order to arrive at consistent measures of evenness/unevenness, it seems indispensable to determine which states are of maximal unevenness and then to assess the position of a given type distribution between states of maximal evenness and maximal unevenness. Since semantically, unevenness implies inequality among type representations, its maximum is reached if all type representations are equally different. For given number of types, this situation is realized if type representations, when ranked in descending order, show equal differences between adjacent types. We term such distributions “stepladders” as opposed to “plateaus” for uniform distributions. Two approaches to new evenness measures are proposed that reflect different perspectives on the positioning of type distributions between the closest stepladders and the closest plateaus. Their two extremes indicate states of complete evenness and complete unevenness, and the midpoint is postulated to represent the turning point between prevailing evenness and prevailing unevenness. The measures are graphically illustrated by evenness surfaces plotted above frequency simplices for three types, and by transects through evenness surfaces for more types. The approach can be generalized to include variable differences between types (as required in analyses of functional evenness) by simply replacing types with pairs of different types. Pairs, as the new types, can be represented by their abundances, for example, and these can be modified in various ways by the differences between the two types that form the pair. Pair representations thus consist of both the difference between the paired types and their frequency. Omission of pair frequencies leads to conceptual ambiguity. Given this specification of pair representations, their evenness/unevenness can be evaluated using the same indices developed for simple types. Pair evenness then turns out to quantify dispersion evenness.</p></","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"70 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2021-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10441-021-09429-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39712626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deepak K. Pattanaik, Amir Prasad Sahu, Vasudevan Lakshminarayanan, Nachieketa K. Sharma
{"title":"The (a)-Wave of the Electroretinogram and Iron-Induced Oxidative Stress: A Model","authors":"Deepak K. Pattanaik, Amir Prasad Sahu, Vasudevan Lakshminarayanan, Nachieketa K. Sharma","doi":"10.1007/s10441-021-09426-y","DOIUrl":"10.1007/s10441-021-09426-y","url":null,"abstract":"<div><p>In photoreceptors of a dark adapted eye, the inward flux of sodium and calcium ions in the outer segment is balanced by the outward flux of potassium ions. But in the presence of light the creation of cyclic guanosine monophosphate in the outer segment decreases. Due to low concentration of <i>cG</i> (cyclic <i>GMP</i>) the channels in the outer segment open relatively less and thus the influx of calcium ion decreases, leading finally to hyperpolarization of the photoreceptors. We have analyzed theoretically the effect of oxidizing iron ions on the photoreceptors. In order to explain the effects of iron-induced oxidative stress, the different molecules and ions involved in phototransduction are quantified leading to a differential equation for calculating the electroretinogram <i>a</i>-wave voltage. The theoretical results are compared with published experimental data. In the presence of light, the iron ions could push outward the similarly charged calcium ions resulting in a small increase in the amount of inward calcium flux. Again, the presence of iron ions generates Reactive Oxygen Species, and ROS could attract the calcium ions which also increases the calcium flux. This will result in a reduction in the amplitude and slope of the <i>a</i>-wave voltage in the electroretinogram. These results are parametrized in terms of calcium ion concentrations. As the amplitude of the <i>a-</i>wave shows how much electrical signal is produced, its reduction indicates reduction in the visual signal. Thus, the increase in iron ions could explain the reduction in the electrical signal due to iron-induced oxidative stress.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"70 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2021-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50019138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Indeterminacy Bottleneck: Implications for Habitable Worlds","authors":"Ian von Hegner","doi":"10.1007/s10441-021-09432-0","DOIUrl":"10.1007/s10441-021-09432-0","url":null,"abstract":"<div><p>It is often assumed that the transition between chemical evolution and biological evolution undergoes a smooth process; that once life has arisen, it will automatically ‘flood’ a solar system body. However, there is no a priori reason to assume that a link between them is a given. The fact that both chemical evolution and biological evolution meet in a single point can be critical. Thus, one may ask: can a world’s environment be favourable for chemical evolution but not for biological evolution, or vice versa? This is an important question worth exploration because certain worlds in the solar system in the past seemed to possess the possibility of chemical evolution, while several worlds in the present seem to exhibit such a possibility. Have such solar system bodies thus been, or are, ‘flooded’ by life? Did they possess the opportunity for biological evolution? The answer depends on the very nature of certain conditions under which evolution occurs, which may indicate that a link between chemical evolution and biological evolution is not automatically realised on a habitable solar system body. Thus, these conditions imply that in the emergence and distribution of cellular life, there exists an indeterminacy bottleneck at which chemical evolution and biological evolution meet through a single cell, whose descendants goes ‘information explosive’, ‘entropy implosive’ and ‘habitat expansive’, which determine whether life moves on to new environments. The consequence is that a world's environment can indeed be favourable for biological evolution, but not for chemical evolution. Thus, even if chemical evolution leads to the emergence of a microbial organism in a world, then it is not a given that such a first life form will be subjected to distribution to other environments; and not a given that its existence will continue in the environment it originated in. Thus, the bottleneck may be one of the decisive factors in the differences between habitable and inhabited worlds.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"70 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2021-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39691051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Toward a More General Understanding of Bohr’s Complementarity: Insights from Modeling of Ion Channels","authors":"Srdjan Kesić","doi":"10.1007/s10441-021-09424-0","DOIUrl":"10.1007/s10441-021-09424-0","url":null,"abstract":"<div><p>Some contemporary theorists such as Mazzocchi, Theise and Kafatos are convinced that the reformed complementarity may redefine how we might exploit the complexity theory in 21st-century life sciences research. However, the motives behind the profound re-invention of “biological complementarity” need to be substantiated with concrete shreds of evidence about this principle’s applicability in real-life science experimentation, which we found missing in the literature. This paper discusses such pieces of evidence by confronting Bohr’s complementarity and ion channel modeling practice. We examine whether and to what extent this principle might assist in developing ion channel models incorporating both deterministic and stochastic solutions. According to the “mutual exclusiveness of experimental setups” version of Bohr’s complementarity, this principle is needed when two mutually exclusive perspectives or approaches are right, necessary in a particular context, and are not contradictory as they arise in mutually exclusive conditions (mutually exclusive experimental or modeling setups). A detailed examination of the modeling practice reveals that both solutions are often used simultaneously in a single ion channel model, suggesting that the opposite conceptual frameworks can coexist in the same modeling setup. We concluded that Bohr’s complementarity might find applications in these complex modeling setups but only through its realistic phenomenological interpretation that allows applying different modes of description regardless of the nature of the underlying ion channel opening process. Also, we propose the combined use of complementarity and Complex thinking in building the multifaceted ion channel models. Overall, this paper’s results support the efforts to establish a more general form of complementarity to meet today’s complexity theory-inspired life sciences modeling demands.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"723 - 744"},"PeriodicalIF":1.3,"publicationDate":"2021-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39467459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhifeng Hao, Jiayou Liu, Biao Wu, Min Yu, Lars H. Wegner
{"title":"Strong Emergence in Biological Systems: Is It Open to Mathematical Reasoning?","authors":"Zhifeng Hao, Jiayou Liu, Biao Wu, Min Yu, Lars H. Wegner","doi":"10.1007/s10441-021-09423-1","DOIUrl":"10.1007/s10441-021-09423-1","url":null,"abstract":"<div><p>Complex, multigenic biological traits are shaped by the emergent interaction of proteins being the main functional units at the molecular scale. Based on a phenomenological approach, algorithms for quantifying two different aspects of emergence were introduced (Wegner and Hao in Progr Biophys Mol Biol 161:54–61, 2021) describing: (i) pairwise reciprocal interactions of proteins mutually modifying their contribution to a complex trait (denoted as weak emergence), and (ii) formation of a new, complex trait by a set of n ‘constitutive’ proteins at concentrations exceeding individual threshold values (strong emergence). The latter algorithm is modified here to take account of protein redundancy with respect to a complex trait (‘full redundancy’). Irreducibility is considered a necessary and sufficient criterion for strong biological emergence; if one constitutive protein is missing, or its concentration drops below the threshold the trait is lost. A definition based on ‘unpredictability’ is dismissed, because this criterion is irrelevant for the evolution of a complex trait, and apparent unpredictability may rather reflect our basic deficits in understanding unless we can provide an unequivocal proof for it. The phenomenological approach advocated here allows to identify hidden rules according to which strongly emergent traits may be organized. This is of high value for understanding the evolution of complex traits which seems to require the saltational advent of all constitutive proteins ‘in one turn’ to arrive at a functional trait providing for an improved fitness of the organism. Rather than being a purely random process, it may be guided by fundamental structural principles.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"841 - 856"},"PeriodicalIF":1.3,"publicationDate":"2021-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39369877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Optimal Control Strategies and Sensitivity Analysis of an HIV/AIDS-Resistant Model with Behavior Change","authors":"Musa Rabiu, Robert Willie, Nabendra Parumasur","doi":"10.1007/s10441-021-09421-3","DOIUrl":"10.1007/s10441-021-09421-3","url":null,"abstract":"<div><p>Despite several research on HIV/AIDS, it is still incumbent to investigate more effective control measures to mitigate its infection level. Therefore, we introduce an HIV/AIDS-resistant model with behavior change and study its basic properties. In order to determine the most sensitive parameters that are responsible for disease transmission with respect to the basic reproduction number and those responsible for disease prevalence with respect to the endemic equilibrium, the sensitivity analysis was established and it was confirmed that the influx rate of people into the infected population and total abstinence from all risk practices and endemic areas are some of the most sensitive parameters for disease spread and disease eradication, respectively. Furthermore, by considering controls <span>(u_1)</span> denoting the government’s intervention in promoting and encouraging behavior change, <span>(u_2)</span> representing intake of balanced nutritional supplementation, and <span>(u_3)</span> connoting antiretroviral therapy (ART), an optimal control problem was developed and analyzed. Before the establishment of the necessary conditions of the optimal control using Pontryagin’s Maximum Principle, we proved the existence of the optimal control triplet <span>((u_1(t),u_2(t),u_3(t)in Phi ,)</span> where <span>(Phi)</span> is the control set at time <i>t</i>,) which has been neglected by many researchers in recent years. Using the Runge–Kutta scheme, the optimal control problem was solved to understand the best combination of control strategies. Using the demographic and epidemiological data for South Africa on HIV/AIDS, a numerical simulation was carried out and results are presented on 3D surface plots. The obtained results suggested that the combination of all the considered control measures is the best method to ensure disease eradication.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"543 - 589"},"PeriodicalIF":1.3,"publicationDate":"2021-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s10441-021-09421-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39263110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Savio Torres de Farias, Francisco Prosdocimi, Gustavo Caponi
{"title":"Organic Codes: A Unifying Concept for Life","authors":"Savio Torres de Farias, Francisco Prosdocimi, Gustavo Caponi","doi":"10.1007/s10441-021-09422-2","DOIUrl":"10.1007/s10441-021-09422-2","url":null,"abstract":"<div><p>Although the knowledge about biological systems has advanced exponentially in recent decades, it is surprising to realize that the very definition of Life keeps presenting theoretical challenges. Even if several lines of reasoning seek to identify the essence of life phenomenon, most of these thoughts contain fundamental problem in their basic conceptual structure. Most concepts fail to identify either necessary or sufficient features to define life. Here, we analyzed the main conceptual frameworks regarding theoretical aspects that have been supporting the most accepted concepts of life, such as (i) the physical, (ii) the cellular and (iii) the molecular approaches. Based on an ontological analysis, we propose that Life should not be positioned under the ontological category of Matter. Yet, life should be better understood under the top-level ontology of “Process”. Exercising an epistemological approach, we propose that the essential characteristic that pervades each and every living being is the presence of organic codes. Therefore, we explore theories in biosemiotics and code biology in order to propose a clear concept of life as a macrocode composed by multiple inter-related coding layers. This way, as life is a sort of metaphysical process of encoding, the living beings became the molecular materialization of that process. From the proposed concept, we show that the evolutionary process is a fundamental characteristic for life’s maintenance but it is not necessary to define life, as many organisms are clearly alive but they do not participate in the evolutionary process (such as infertile hybrids). The current proposition opens a fertile field of debate in astrobiology, epistemology, biosemiotics, code biology and robotics.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"769 - 782"},"PeriodicalIF":1.3,"publicationDate":"2021-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s10441-021-09422-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39261790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Factors in Protobiomonomer Selection for the Origin of the Standard Genetic Code","authors":"Alexander I. Saralov","doi":"10.1007/s10441-021-09420-4","DOIUrl":"10.1007/s10441-021-09420-4","url":null,"abstract":"<div><p>Natural selection of specific protobiomonomers during abiogenic development of the prototype genetic code is hindered by the diversity of structural, spatial, and rotational isomers that have identical elemental composition and molecular mass (M), but can vary significantly in their physicochemical characteristics, such as the melting temperature T<sub>m</sub>, the T<sub>m</sub>:M ratio, and the solubility in water, due to different positions of atoms in the molecule. These parameters differ between <i>cis-</i> and <i>trans</i>-isomers of dicarboxylic acids, spatial monosaccharide isomers, and structural isomers of α-, β-, and γ-amino acids. The stable planar heterocyclic molecules of the major nucleobases comprise four (C, H, N, O) or three (C, H, N) elements and contain a single –C=C bond and two nitrogen atoms in each heterocycle involved in C–N and C=N bonds. They exist as isomeric resonance hybrids of single and double bonds and as a mixture of tautomer forms due to the presence of –C=O and/or –NH<sub>2</sub> side groups. They are thermostable, insoluble in water, and exhibit solid-state stability, which is of central importance for DNA molecules as carriers of genetic information. In M–T<sub>m</sub> diagrams, proteinogenic amino acids and the corresponding codons are distributed fairly regularly relative to the distinct clusters of purine and pyrimidine bases, reflecting the correspondence between codons and amino acids that was established in different periods of genetic code development. The body of data on the evolution of the genetic code system indicates that the elemental composition and molecular structure of protobiomonomers, and their M, T<sub>m</sub>, photostability, and aqueous solubility determined their selection in the emergence of the standard genetic code.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"745 - 767"},"PeriodicalIF":1.3,"publicationDate":"2021-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s10441-021-09420-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39201496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What is Causal Specificity About, and What is it Good for in Philosophy of Biology?","authors":"María Ferreira Ruiz","doi":"10.1007/s10441-021-09419-x","DOIUrl":"10.1007/s10441-021-09419-x","url":null,"abstract":"<div><p>The concept of causal specificity is drawing considerable attention from philosophers of biology. It became the rationale for rejecting (and occasionally, accepting) a thesis of causal parity of developmental factors. This literature assumes that attributing specificity to causal relations is at least in principle a straightforward (if not systematic) task. However, the parity debate in philosophy of biology seems to be stuck at a point where it is not the biological details that will help move forward. In this paper, I take a step back to reexamine the very idea of causal specificity and its intended role in the parity dispute in philosophy of biology. I contend that the idea of causal specificity across variations as currently discussed in the literature is irreducibly twofold in nature: it is about two independent components that are not mutually entailed. I show this to be the source of prior complications with the notion of specificity itself that ultimately affect the purposes for which it is often invoked, notably to settle the parity dispute.</p></div>","PeriodicalId":7057,"journal":{"name":"Acta Biotheoretica","volume":"69 4","pages":"821 - 839"},"PeriodicalIF":1.3,"publicationDate":"2021-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s10441-021-09419-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39177745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}