Monday, October 31, 2022

The Relational Hypotheses of Earth’s Societies

The Relational Hypotheses of Earth’s Societies

Introduction

The earth’s society builds, supported by ‹men’s inventions›, with relevant abstract features and intellectual spins, adding personal, communal and sovereign frame standards. The extant ‹nations› distinguish by idioms and governments, enjoying entitled administration and ruling layouts. These characterise the ‹civilisation› idiosyncrasy, assuming peculiar entrustments, such as:
a) Divine running: the material world has governance in upper godlike reality;
b) Natural backdrop: the universe has inner ruling, due to cosmos’ regularity;
c) Interpersonal assignment: the collective steering refers to endorsed edicts.
The divine and the natural ‹laws› are total truths, with upper or inner worth, out of man’s span; they offer consistent ‹faiths›: the former, once transcendence is recognised proposition; the latter, if ‹information› immanence qualifies the material reality. The human ‹laws› are contingent forms, with provisional meanings, linked to current contexts. The ‹faiths› in ‹total dualism› or in ‹qualified monism› are a priori guesses; they deserve a posteriori justifying trials, weather theory foundation is expected. The transcendence cannot enjoy direct perception; the cogent immanence admits the ‹matter/information› coherence, vindicating the cosmos’ physics. The third sample allocation has only posteriori evidence, limiting the build-up of ‹knowledge› and ‹science› to what learned and systematised, having agreement of the fellow researchers.
We do not deal with total laws; we just acknowledge provisional conjectures [1-5]. In the study, the third entrustment is usual pick, to depict the earth’s society, with the account of how the humankind organises the ‹civilisation› questions. The analyses consider the ‹relational hypotheses›, which explore the personal teaching/ learning, copying/emulation, training/appraisal, etc., to implement the series of software/hardware outfits of the human peoples [6- 11]:
• Community organisation: internal infrastructures, for balanced private/public running;
• Legality frames: political substructures, for civil behaviours and communal enactments.
• Authority schemes: autonomy and sovereignty figures, for independent administrations;
• Nation-state operation layouts, to achieve comparative civic and executive performance;
• Mutual establishments: economic substructures, for supply chains and trade provision;
• Productive setups: business, agrarian and industry devices, for goods and stocks making;
• Conversion and restructuring plans: technical and management changes, for throughput. The earth’s society is conservative and intellectual invention, imagining complex sets of mental surveys, to deal with multiple substructures and critical establishments. These software/hardware setups concern the regulation of communities, through internal rules and external safeguards. The idea of structured assemblies brings to rubrics, directives, duties and obligations, all abstract signs, further than material pieces. The intellectual (or spiritual) cues, in keeping with the three starting allocations, have traditionally entailed typifying situations:
• Divine ‹laws›, when ‹spirit› has transcendent connotation, to grant absolute rate;
• Natural ‹laws›, if ‹matter/information› joining assures kami-driven total worthiness;
• Human ‹laws›, if ‹qualified agreement› leads to shared sanctioning of given edicts.
With the molecular biology, genome and its information merge: we only need decoding jobs; the natural ‹laws› involve encoded deterministic issues and ‹spirit› degrades to animism, without upper independent steering. With the human intellect, ‹spirit› converts in mind activity, to handle concepts, imagined and shared as community prerequisite. The survey of the software/hardware setups leading the earth’s society, hereafter, analyses the above listed main formats [12-16].

The Core Formats of Earth’s Society

The earth’s society has anthropoid centering, due to interpersonal talents, i.e., ‹idiom›, ‹market› and ‹law›, Figure 1, based on mental activity, once the human ‹mind› forms by learning and training. In some formal approaches, the ‹mind› format has absolute worth, assigning divine/natural origin to the extant ‹legality› frames. These happen as odd ‹beliefs›, but we have already left total trusts, for contingent guesses, when dealing with the human ‹law› frames [17-21]. The earth extant peoples distinguish by idioms and governments, enjoying joint political and economic layouts. The compositions appear native arrangements, with recent worries on financial flops due to lop-sided split-sovereignty and on wealth inequality of the citizens at the nation and at the world ranges. The hindrances are summarised by assessed facts, with well-known essential hints. Yet, the initial discussion of the current formats permits grasping how the earth’s society develops on ‹relational› skills.

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Figure 1: The earth’s society: anthropoid setups.

Community Organisation

The earth is negligible planet in the universe, where life courses occur, ensued by living beings with brain-to-mind talent, i.e., intellect. The combined oddities establish complex issues [22-27], by:
• Agentive trails: gene evolution, ethnic greediness, active rivalry, clan solidarity;
• Relational trails: meme fruition, emulation/simulation abilities, wise rationality.
The biology has standard effects: gene evolution› creates many living species, aiming at better-adapted samples, (Figure 2). The ‹mimicry› requires self-awareness, spotting construct as identifying traits. The cognizance courses occur, when mutual completion establishes by personal education with formal gears. The earth’s relational model, typically, avails of three intellection mechanisms:
• Communication tools: the population language and the clan dialect;
• Market tools: the domestic supply and budget balancing by trading;
• Governance tools: the country’s autonomy via sovereign authority.

The ‹selfish gene› affects the relational model, bringing about ‹closed societies› in competition, qualified by idiom and sovereign. The rationality› can suggest switching to ‹altruist meme›, leading to ‹open societies›, at global village consistency. Nonetheless, the ‹closed society› is classic choice: we distinguish citizens from foreigners; the split-sovereignty is coherent standard, to deal with lots of independent ‹nation-states›. The sovereignty happens having citizens’ origin, via ‹Constitution›, which establishes the limits of the government’s acts: the law authenticity resides in citizens; the government has delegated relative power. The ‹people sovereignty› appeared in history periods, when total readings, were no more plausible. Indeed, the authenticity, along centuries, undergoes changes, entailing divine or racial investitures, say, godlike or ethnic worth of the ‹nation›, implying sharp communities’ endpoints.

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Figure 2: Hardwae/software formats of the earth’s society.

Legality Frames

The relational interactions involve mimicry skills, each individual being capable to figure out his intellectual duplication. The meme fruition entails the said mechanisms, at three layers:
a) Personal, to learn, practice and transmit the communication idiom and knowledge;
b) Domestic, to manage the family/home sources and accounts by shared marketing;
c) Civic, to fulfil the tribe/nation’s activities and duties, in respect of the indorsed acts.
The three spheres have contingent worh, linked to the timely earth’s society settings. The inner one is interpersonal: it establishes the ‹mind›, with the abstraction talent to objectivise acts, goals feelings and layouts. The next one deals with ‹open societies›, soon, taking out the linked ‹closed society›, into which organising effective legal frames, for the operation political structures [28- 32]. The recent political spheres follow split-sovereignty models, in the ‹capitalism›, with separate ruling than wealth. The ‹income inequality› is actual concern; the ‹fortune inequality› is intricate query: the ‹affluence› of individuals says that the accumulation, due to their activity, is possible, with allowed transmission (within a family); the ‹assets› of enterprises mean that the build-up, due to the tied activity, is qualifying result of the organised business.
The ‹accruals› build up as ‹wealth expansion› or ‹growth›, leading to ‹improved opulence›. The outcome is measured by ‹money› or, using an established designation, by ‹financial capital›, under ‹sovereign› ruling. The ‹wealth› of nations, besides state property (Latin ‹demanium›), assembles private ownership with (public) Treasury (UK Exchequer): the fiscal income links to the gross national product, GNP. If the government expenditures exceed the revenue from taxes, the Treasury shall get into debt, issuing bonds or other sureties. The country’s riches are marginal opulence; the fiscal earnings are usual treasury means, managed as ‹financial capital›, (Figure 3), by legal features

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Figure 3: The legality enacted by sovereign natio-states.

Authority Schemes

The personal/domestic/civic layers allow sovereign political setups, as if the hierarchy aimed and exclusive performance distinguishes the nation state’s spheres. The enabled effectiveness is competition option and the operation layouts distinguish due to the civic and executive planning. The recent events oppose ‹communism› to ‹capitalism›, i.e., state-ruled vs. private-owned wealth. In any case, the ‹nation-state› is basic reference, enjoying ‹split-sovereignty› and ‹democracy› say, the ‹people authority›, (Figure 4), with contingent worthiness [33-38]. The self-ruling governance gives political and economic autonomy. In the picture, the ‹income› allows finance transactions; ‹wealth› links to the ‹stored capital›, with money worth: individuals’ ownerships, companies’ assets and governmental treasury, if we follow the ‹capitalism›, with private vs. public ownership. In the ‹communism› reading, all is communal, under the central nomenclature steering; for a while, the XX century› fancied hinting the community track to be superior feat.

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Figure 4: The administation independence allows hierarchy authority.

The millennium starts, showing self-disintegration of the conjured enhanced frame. The XXI century ‹capitalism› is hybrid setup, with global urges: ‹communication›, ‹economy› and ‹ecology›. The ‹global communication› provides plenty options, with private profits (known list) and public advantage (including control of citizens’ interactions and messages!). The ‹global economy› means that the ‹split-sovereignty› is non-sense, if the financial independence does not exist anymore: the biasing monetary guiles (Keynes’ manoeuvers, currency devaluations, etc.) are two-edge tricks, untying ruins. The ‹global ecology› is XXI century drawback, leading to downfalls, if out of sustainability plans. These brief cues show that hybrid ‹capitalism›, also, needs revisions.

Teamwork Patterns

The human ‹culture/ethics› syntheses distinguish due to cooperative accomplishments, leading to combine plans, aimed at useful results, with social or technical traits, (Figure 5). The previous points offer cues the authenticity and accounting backings. The supply chain speciality requests, as well, front-end practical material transformations, to obtain useful products. These substructures have processing and economic worth, as the interpersonal acts enable fit issues. The relational options, language, trade and legality, enjoy combined gene and meme trails. The divine spirit is old spur to intellect. In the Darwinism, the gene evolution offers suggestions. Further hints need be added, to summarise the state of the art on the subject, to show the overall complexity of the topics [39-43].
In modern ages, the relational structures stabilise at three levels:
a) The outer political, with the ‹nation-state› invention and the related legality;
b) The middle domestic, with mutual civic establishments and trade provisions;
c) The inner subjective, with agreements on worthy ‹private› and ‹public› roles.

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Figure 5: Interpersonal deeds for supply chauns.

The arrangements are men’s invention, moving from idioms for shared grasp, market for joint business and authority for common officialdom. The red tape is vital, only if parallel actors work. The trade relevant, especially after agrarian/industrial revolutions, with mass-production. Yet, the relational ability establishes with the spoken/written languages, which allow deep understanding and multiple appreciation. The built ‹knowledge› allows sophisticated novelties:
d) The mass-outputs, through the (notably agrarian and industrial) revolutions;
e) The artificial life/intelligence yields, by modulating the cognitive revolution.
The collaborative teamwork is meme fruition chance, stopping gene selfishness, as ‹rationality› shows possible alternatives, towards betterments. The revolutions are bets, with contingent value; a posteriori, only, we become aware of profits. The cooperative thinking is further fulfilment, with ways to the intellectual conception of useful operations and structures.

Productive Outcomes

The work-Organisation revolutions implement software/ hardware setups, with multiple objects and relevant improvements. The ‹inventions› cover mental deployments, fully building intellectual construal, with interpersonal teamwork achievements. Example issues cover:
a) Social enhancements, since the efficiency directly affects the results’ spheres;
b) Legal structures, with creation of ‹nation-state› or other analogous institutes;
c) Political ideas, connecting the domestic assemblies with civic and global links;
d) Technical options, discovering synthetic rulings, to justify the expected issues.
The work-organisation deeply affects the agrarian/industrial upheavals, when the new orders, with independent administrations of split-sovereign countries establish. The outcome brings to the competition of parallel ‹nation-states›, at unlike ‹progress› phases. The ‹revolutions› are technical mark, showing the society’s effectiveness of the current local civilization. The ‹productivity› is talk unknown in wilderness; it becomes critical comparative figure. The ‹progress›, however, is relative quantity: the choice can have preferences, but cannot be sure of an upgrading; our example issues are mind’s ideas, not cosmos’ information [44-49] (Figure 6).

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Figure 6: Organisation/mechanisation of the productive setups.

Operation Workings

On our negligible planet, the earth’s society has anthropoid driver, because the ‹intellect› limits to men. The ‹progress› is clever choice: ‹obvious›, if ‹possible›: the ‹productivity› is magic aim; the ‹entropy› shows that limits exist. We might only inspire to anthropic doctrines and we may look at iterating as much as possible the ‹life› and ‹intelligence› singularities via artificial doubles, (Figure 7). The analyses are, possibly, fantastic and, just, used to provide hints. The ‹intellect› or, perhaps, the ‹spirit› looks at the ‹conversion› towards artificial life/intelligence and then, at ‹restructuring› the originally planned ‹technical and management changes›. The images lead to assemble:
a) The relational skill exploration: idiom/symbol, market/trade and authority/law;
b) The matter/knowledge forward/backward ‹conversion› of engineering chores;
c) The design synthesis, effecting natural provisions through artificial replications.

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Figure 7: Anthropoid emulation of technical operation processes.

The men’s society develops because of the ‹relational› competences, fashioned and specialized by coaching, tutoring and training the children. The preliminary civilization enjoys substantial lack of restrictions, with loosely interacting tribes, easily moving to set-apart locations. The history age tells about countries and sovereigns in competition, i.e., wars, winners and losers. The periods-to -come show the earth approaching a common global village, in which we need cohabiting, keeping the safeguard of goods and objects we have to share. The future deploys with new challenges: the saving, cutback and remediation are investigated by moving many material processes, to cognitive additions and transformations on intangibles, to minimize the entropy contexts [50-55].

The Earth’s Society Economy/Ecology Defies

The ‹global› defies are curious outcomes, with series of sidefacts, making difficult to excerpt some simple remedy, due to the cross-link of situations. The present analyses address the fact to deal with human communities and look at explaining the ‹civilization› as direct organized outcome of ‹intelligent› operators in their current conditions. The picture entails the useful earth’s sources or ‹natural capital› and the ‹thinking heads›, i.e., the operative skills of men or ‹human capital›, based on agentive and rational talents, to create artificial results. The conventional assessments is rooted in ‹money› or ‹financial capital›, synthetic trick, dressing balanced bargains, once adding up the ‹technical capital›, to include men’s invented procedures and contrivances, (Figure 8). Curbing fact is today the ‹natural capital›: the ‹growth› is ‹transformation-based›; the ‹entropy› presumes decay and the ‹wealth expansion› cannot be endless, but the negative effects will propagate the global village over. The ‹global› defies, simply, show the end of ‹our human cycle› [56-61].

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Figure 8: The basic ‹capitals› of the relational modes.

The ‹relational modes› amplify the reality, adding images, links and qualities, i.e., symbolic cues fulfilling, however, the characterisation of the pending occurrences. The multiple accounts, dealing with idiom (to talk), market (to trade) and legality (to enact), show that these modes build on joint interactions, or that the ‹human mind› starts forming, when cross-faced and coached. Linkage and education reflect on the basic ‹capitals›, giving evidence to some meanings and symbols. We recall example hints, to manage the said multiple accounts, in view of future challenges.

Relational Modes

The ‹human progress› is open query. The financial packing (individuals’ ownerships, companies’ assets and governmental treasury) are risky blurs, if just rooted in the ‹contrived› sovereignty of the ‹nation-states›. The dominance gives authority to tax the subjects moving most of the extant gross national product, GNP, to consumption under public rule. If the ‹nation-state› running takes over 50% GNP, we are halfway of ‹communism›. The figure is hot: residual wealth runs private, by cooperation recipes or sunken trade forms. In its place, the nomenclatures, fittingly, organize over self-adaptive hierarchies: the ‹capitalism› vs. ‹communism› or GNP ratio to alter from ‹private› to ‹public› management, has country’s officialdom, more than safe track. The no ahead way is severe query: with ‹communism› (Gorbachev) glasnost, the ‹private› economy returns, since the earlier ‹public› dominance aimed at self-disintegration; with ‹capitalism›, split-sovereign countries make debts with potent suppliers, for amounts exceeding GNP safe ratios (out of constitutional bonds).
The flexibility in debt repayment is ambiguous help, later turned in planned abuse. The ‹nation-state›, with 50% GNP required by ‹public› consumption and national debt equal or bigger than the GNP, is not viable; it will end in downfall, due to government’s decision. The symbolic detection of safe ratios, typically, links to the ‹sovereignty› concept with ‹public› force. Steady cut-off identifies by riven-governance and divided-native/training assemblies, as if ‹independence› or ‹autonomy› is divine or ethnic mark. When such absolute reading is left out, the legality order, (Figure 9), develops in parallel, forming factual ‹public› relational layers, out of the ‹private› ones [62-67].

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Figure 9: Interpersonal ‹symbolic› joint unearthning.

Outcome Release

The sketch, if the relational options are pivotal truths, reveals ‹natural laws›, say, ‹information› coded within the cosmos. The readings entail monism, along racial and ethnic lines. In alternative, the total dualism refers to transcendent reality, say, ‹god driven occurrences›. The modern age, by explicit or implicit schemes, propose that the European countries practice split-sovereignty, sort of noteworthy achievements via competitive rivalry proficiency. The nation ‹closed society› becomes tool, to tell how and why the success appears rewarding given peoples. Our analyses cannot trust pivotal truths: we might list singularities, carrying contingent worth: ‹life›, prompting repetitions; ‹intellect›, predisposing abstraction. Then, ‹gene evolution› creates the many living specie; ‹meme fruition› establishes the a posteriori ‹relational› framework (without a priory total truths) [68-73]. A priori godly or ethnic partitions bring to rivalry, with side belief, such as ‹Hobbs’ rule›.
War is natural feature, deemed to get supremacy to best-fit groups, because managing ‹closed societies›, in which efficient hierarchies establish. Competition aims at forming top-down authority, indorsing solidarity tests, to foster the clan cohesion. The global economy falloffs mix the nations’ interests: the cross-effects cannot grant the planned steering. A posteriori factual appraisals lead to steady pictures, such as ‹Kant’s rule›: the cooperation adopts altruism habits in ‹open society›. The global ecology shows crosslinks, requiring coupled management, (Figure 10), to describe the ‹outcome›. That result tells that the world citizen aims at global village, with bottom-up authenticity.

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Figure 10: From ‹pivotal truths›, to ‹coupled management›.

Shared Advance

The lose reliability of ‹pivotal truths› with godly or ethnic foundation links with the three-rank relational modes: language (to dialogue), business (to market) and law (to govern). The personal interface ripens, through education practices, towards ‹closed society› solidarity or ‹open society› altruism, if we make use of the above hints. The millennium changes are clear. If global economy brings in conflictual limitation to the sovereignty fragmentation, the global ecology fully eliminates disjointed decision keeping. The thinkable growth requires global village uniform legality, (Figure 11), or the earth needs unchanging governance, maintaining unbroken protection [74-79].

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Figure 11: From ‹riven governance›, to ‹common legality›.

Split-sovereignty is nonsense: the ‹closed societies› swap into a single ‹open society›, in which the relational construal has to work along the rational trail of the altruism, as the transparency of the ecology data tells the haughtiness of the local freedom. The resort to the ‹nation-state› rivalry stops. Instead of ‹mors tua, vita mea›, all move together towards death. The altruism is thrifty remedial, when ‹sustainable corporations› act together with ‹certification bodies›, enabling ‹big society› consistency. The riven governance might deal with protected economy; the global ecology shows that no marginal benefit shall distinguish to sheltered people, since no privilege can exist at the ecologic viewpoints. What we do will repeat with alike hindrances: the ‹altruism› does not tell that are fond of the aliens; it simply says that we avoid poisoning our existence.

Altruism Cues

The citizen of the world does not limit to closed clans; he aims at the global village, built on the ‹big society› options, with bottom-up authenticity. The fact tells that the relational links deploy a set of effects: to enable genome-encoded plans; to resort to intellect options; to compare the on-progress results; to show decision-like talent. The ‹rationality› develops when the interaction level is complex: the gene selfishness does not help; the meme altruism provides hints to address ways-out and to select leads. The relational construal brings forth comparisons, judgments and choices. The meme trail tracks simulation and emulation, since the intellect options add abstract images by mimicry and copy, supporting phantasy specifications, with clearly identified merits [80-85]. The global economy is current request, when segmented markets establish. The global ecology switch in the new selflessness directions, once curtailing cognition follows. The analyses, involving the global village, address the ‹open society› layout: we cannot deal with social or political rights, reserved to the citizens of given countries (Figure 12). The ecology requires removing the privileges, so that, at the interstate range, the civil obligations bring about full altruism compensation. The result is, perhaps, a bit too complex if the split-sovereignty persist. The question is left open, and the third relational range of the ‹legality› is, accordingly, to revise.

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Figure 12: The ‹altruism› vs. ‹check, appraisal and pick›.

Conclusion

The ‹relational hypotheses› offer hints on different purposes. In the present survey, the central drive aims at justifying the factual interpersonal human capabilities, which establish the substance of the civilisation. The analyses suggest complex interpretations, since the images and concepts in the human minds form modify and sore-up with contingent force, but clear evidence [86,87]. Pictures and ideas have readings, in which we may directly recognise strong facts and transitions:
a) The core setups, listing formats that tell the human software/ hardware edges.
b) The critical drafts, giving details on the current economy and ecology settings.
These complex interpretations are, however, imperfect, as the core setups remain contingent, without total truth and the critical drafts are liable priority with restricted efficacy. In the survey, the absolute pictures, done by monism (and information immanence) or total dualism (and godly transcendence) have explicit mention, keeping merely figurative functions. The steady formats can enjoy right acknowledgements, e.g., trusting the formerly exemplified seven figures. At the point, the dangerous economy/ecology traits become serious confrontation, with the further epitomised five traits. The discussion on the subject, certainly, does not stop here [88-91]. The analyses need combining the steady core formats, with the looming critical defies. By now, we can move back to the ‹relational hypotheses›, trying to detail the changeovers to face. The pick has separately to address the situations with explicit links to the entropy trends, either the control on saving/recovery imperatives for ‹sustainability›, namely:
a) The swap into deteriorated surrounds and unhealthy political institutes;
b) The planned reclamation/recycling to yield ordered headway outcomes.
Formal ‹natural laws›, with coherent structure, perhaps, identifies the core setups: the written comparisons are difficult to assess by absolute data. The second research line has just provisional worth, but the appraisals are more consistent. Can we expect programmed ‹sustainability› issues? The global ecology problems imply negative answers, if aimed at ‹absolute› construal. ‹Entropy› is fundamental truth of the cosmos’ inner information: men’s devised tricks to improve efficiency enhance, as well, waste and speed up decay. We may trust in ‹miracles›: total dualism tells that degeneracy affects matter, not spirit; the man’s civilization can be almighty’s design. The ‹faith› in total truths simplifies our guesses, but we, only, relay on our invented ‹science›, say, ‹knowledge›, possibly, a posteriori set by the ‹falsification rule›, just, allowing ‹provisional› readings. The line does not enjoy fixed logic: the weak course, however, can explore operation dualism, once ‹singularities› occur and open peculiar options. On the earth, the ‹life› and the ‹intelligence› are odd discontinuities, bringing in proper agentive and rational wherewithal, i.e., the bases of the men’s civilization.
The civil headway, built by ‹contingent› construal, is provisional or conditional upshot; its ‹sustainability› is not a priori certainty, but just a posteriori upshot. The outlined study offers cues on the subject, telling that ‹sustainability› is restricted and temporary outcome, as any other men’s conceived invention. The social advance combines communication and business with political setups, in view to manage ordered localised ‹nation-states›, each one with its govern. In the account, the parallel countries refer to their preexisting traditions, being obvious that the split-independence does need proof, if, just, the earlier autonomy exists. The ‹sovereignty› does not need explanations: the ‹authority› and the ‹closed society› enjoy acknowledged consent. The present investigation looks at the ‹relational modes› affecting the men in their earth’s life. The enquiry has particularly relevant outcomes, as it permits identifying really important men’s traits: the language invention, the market practice and the authority instigation.
The accounts do not provide absolute proof that the three relational links necessarily develop; the provisional ties are verified hypotheses, once the language finding, the market drill and the authority urging are on duty facts, with a posteriori check. The ‹hoc post hoc, ergo propter hoc› logic cannot be used, however, the links between the three ‹relational modes› is stressed. In alternative, the enquiry is separately addressing the said ‹relational modes›, as if the links shall not establish because of fit equivalence at the interpersonal rehearsal. But: idiom, barter and kerb are mind construal, with fit consistency: the current search shows details more and more meme fruition pertinent, i.e., linked to the rational deployments, after the agentive settings of the gene evolution. The earth’s society organization according to suitable ‹relational› knacks, in which speech and talking or market and barter or authority and kerb are advantages for the citizens’ understanding, manoeuvre and governance, is object of examinations along the study, with helpful niceties.
The details easily connect with ‹immanent information› or with ‹godly pictures› if absolute data are in our availability. These are, surely, imaginary forecasts; the niceties happen being contingent facts, as the ‹relational› talents characterise the humanity and enjoy provisional worth, not total truth. In the inspections, speech and talking or market and barter or authority and kerb are unbelievable brainchildren, maybe, easier to acknowledge, if ‹immanent information› or ‹godly pictures›. The ‹relational› hypotheses, thereafter, have sketches with consistent remarks, but out of necessities: we do not have hints that justify idiom, trade or authority; we say these happenings build and, in parallel, the ‹human cognizance› is awkward narration, with peculiar, induced effects [92-97]. It is hard to tell how far ‹cosmos› and ‹earth› distinguish. In the present analyses, the ‹biology› and the ‹cognition› appear strong occurrences, proposing ‹gene evolution› and ‹meme fruition›, in view of ‹life› adaptation because of agentive peculiarities and ‹intellect› completion according to rational distinctiveness.
We, perhaps, trust in ‹laws of the nature› with inner causality structure; yet: evolution is more factual: it brings the inner changes, to growth cycles and fitting editions. In like measure: fruition has truthful power: it leads the inner talent to emulation and simulation acts and to relational deployments, with rational assessments and decision-making traits. The resort to interpersonal gifts allows exploring parallel images and appraisals and balancing the crossideas or mind by-products. The mental spinoffs deal with the formation and the controlling of the ‹human knowledge›, i.e., the management of our ‹understanding› about what we discern occurring around us. We think to observe, comprehend and partake when involved in physical transformations. The collected data, acknowledged phenomena and designed actions are reliable or truthful notions, so that the ‹human knowledge› happens duplicating the cosmos’ information (in current requests). In conclusion, the ‹relational hypotheses› seem offering the way to bypass the access to ‹total truth›, by factual access to truth, since the interpersonal gifts support operation alternatives.

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Saturday, October 29, 2022

Disorders of Energy Metabolism in Neurons of the Cerebral Cortex During Cerebral Ischemia

Disorders of Energy Metabolism in Neurons of the Cerebral Cortex During Cerebral Ischemia

Introduction

In cerebral ischemia (CI), a chain of pathogenetic disorders develops in its structures, among which one of the leading is energy deficiency, which leads to the development of cellular pathology [1,2]. The work of enzymes, including sodium-potassium ATPase, is disrupted, leading to an imbalance of ions and cerebral edema [3-6]. A number of molecular markers of the energy activity of mitochondria are known, among which one of the main markers is ATP synthase - an integral protein of the inner mitochondrial membrane that carries out the reaction of ATP formation from ADP [7,8]. Mitochondrial ATP synthase plays an important role in the differentiation of stem cells, promotes the formation of mitochondrial cristae by dimerization and specific regulation [9- 11]. The enzyme belongs to the alpha / beta ATP synthase family. Consists of two structural domains (F1 - extramembrane catalyst and F0 - membrane proton channel), connected by a central rod consisting of γ, δ and ε subunits [12-15], and together with the oligomer of the membrane subunit representing the rotary domain of the enzyme [1,4,7,16,17].Elucidation of the mechanisms of the development of energy deficiency in ischemic damage of varying severity is advisable for detailing the pathogenesis, the ratio of damage and compensation processes in СШ. The aim of the study was to assess changes in the content of ATP synthase in the parietal cortex and hippocampus of the brain of rats with ischemia of varying severity in a comparative aspect. For this purpose, the changes in the content of ATP synthase in rats with partial, subtotal, stepwise subtotal and total СI were studied [3].

Methods

The experiments were carried out on 88 male outbred white rats weighing 260 ± 20 g in compliance with the Directive of the European Parliament and of the Council No. 2010/63/EU of 22.09.2010 on the protection of animals used for scientific purposes.CI was modeled under conditions of intravenous thiopental anesthesia (40-50 mg/ kg). Total cerebral ischemia (TCI) was modeled by decapitation of animals. The brain sampling was carried out 1 hour and 24 hours after decapitation to study tissue respiration of mitochondria, and also after 1 hour to determine the content of ATP synthase. Subtotal cerebral ischemia (SCI) was modeled by simultaneous ligation of both common carotid arteries (CCA). The material was taken after 1 hour to determine the content of ATP synthase. Graduated subtotal CI (GSCI) was performed by sequential ligation of both CCA with an interval of 7 days (subgroup 1), 3 days (subgroup 2), or 1 day (subgroup 3). The sampling of material was carried out 1 hour after ligation of the second CCA in each of the subgroups. Partial cerebral ischemia (PCI) was modeled by ligating one CCA on the right. The sampling of material was carried out 1 hour after the operation [3,18].
Determination of the content of ATP synthase was carried out by immunohistochemical method using monoclonal antibodies. For this purpose, after decapitation, the brain was quickly removed from the rats, pieces of the cerebral cortex were fixed in zincethanol- formaldehyde at + 4°C (overnight), then embedded in paraffin. Paraffin sections with a thickness of 5 μm were prepared using a microtome and mounted on glass slides. The preparations were processed according to the protocol of immunocytochemical reaction for light microscopy, excluding the procedure of thermal unmasking of antigens. To determine the immunoreactivity of the molecular marker of mitochondria ATP synthase (complex V that forms ATP from ADP), primary monoclonal mouse antibodies (Anti- ATP5A antibody, Abcam, UK, ab. 14748) were used at a dilution of 1: 2400 at + 4°C, with an exposure of 20 h in a humid chamber. To detect bound primary antibodies, an EXPOSE Mouse and Rabbit specific HRP/DAB detection IHC kit Abcam (Great Britain, ab. 80436) was used. The immunoreactivity of ATP synthase was studied in the cytoplasm of neurons of the fifth layer of the parietal cortex and neurons of the CA1 field of the hippocampus in immunohistochemical preparations based on the optical density of the chromogen sediment using an Axioscop 2 plus microscope (Zeiss, Germany), a digital video camera (Leica DFC 320, Germany) and an image analysis program ImageWarp (Bitflow, USA).To prevent systematic measurement errors, brain samples from the compared control and experimental groups of animals were studied under the same conditions.
As a result of research, quantitative continuous data were obtained. In connection with the use of small samples with an abnormal distribution in the experiment, the processing was carried out by the methods of nonparametric statistics using the licensed computer program Statistica 10.0 for Windows (StatSoft, Inc., USA). Data are presented as Me (LQ; UQ), where Me is the median, LQ is the value of the lower quartile; UQ is the upper quartile value. Differences between groups were considered significant at p <0.05 (Kruskell-Wallis test with Bonferoni’s correction) [19].

Results

In TCI, a decrease in the content of ATP synthase, which characterizes the state of the V-complex of the electron transport chain, was noted in comparison with its level in the control group - by 74 (66; 86) % in the parietal cortex, p<0.05 and by 70 (54; 81) % - in the hippocampus, p <0.05 (Table 1, Figures 1 & 2). At the same time, there were no differences in the content of the enzyme in the parietal cortex and hippocampus (p>0.05).Compared with the value in the “control”, in the SCI group, the content of ATP synthase decreased by 45 (38; 53)% - in the parietal cortex (p <0.05) and by 39 (31; 46)% - in the hippocampus (p<0.05).Compared to the level of the value in the “TCI” group, the content of ATP synthase in rats with SCI was higher in the parietal cortex by 57 (46; 61)%, p<0.05 and by 38 (32; 43)% - in the hippocampus, p<0.05.The decrease in the content of ATP synthase in rats with SIGM was less pronounced than in rats with TCI - by 29% in the parietal cortex (p <0.05) and by 39% in the hippocampus (p <0.05).With PCI, there was a decrease in the content of ATP synthase, compared with the value in the control group - in the parietal cortex by 21 (13; 32)%, p <0.05, in the hippocampus by 8 (4; 13)%, p <0 , 05.

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Table 1: The content of ATP synthase in the cytoplasm of neurons in the parietal cortex and field CA1 of the hippocampus of rats with total, subtotal and partial cerebralsischemia,sMes(LQ;sUQ).

Note: * - p <0.05 compared with the “control” group, # - p<0.05 compared with the “TCI” group, + - p<0.05 compared with the “SCI” group, α - p<0.05 compared with, compared with the 1st subgroup of SCI,
β - p<0.05 in comparison with the 2nd subgroup of GSCI. TCI - total cerebral ischemia, SCI - subtotal cerebral ischemia, PCI - partial cerebral ischemia, SSCI - stepwise subtotal cerebral ischemia, sg – subgroup

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Figure 1: The content of ATP synthase in the cytoplasm of pyramidal neurons in the parietal cortex of rats with total (TCI), subtotal (SCI), stepwise subtotal (GSCI) and partial cerebral ischemia (PCI). Digital micrograph. Magnification x 40.
Note:
• Subgroup 1 - the interval between CCA dressings 7 days
• Subgroup 2 - the interval between CCA dressings is 3 days
• Subgroup 3 - the interval between CCA dressings 1 day

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Figure 2: The content of ATP synthase in the cytoplasm of pyramidal neurons of the CA1 field of the hippocampus of rats with total (TCI), subtotal (SCI), stepwise subtotal (GSCI) and partial cerebral ischemia (PCI). Digital micrograph. Magnification x 40
Note:
subgroup 1 - the interval between CCA dressings 7 days
subgroup 2 - the interval between CCA dressings is 3 days
subgroup 3 - the interval between CCA dressings 1 day

At the same time, compared with the value in the “TIGM” group, the content of ATP synthase in the cytoplasm of neurons was 70 (66; 85)% higher in the parietal cortex (p <0.05) and by 58 (41; 76)% - in the hippocampus (p <0.05), and compared with the value in the “SCI” group - by 28 (19; 38)%, p <0.05 and 35 (27; 42)%, p <0.05 , respectively. A decrease in the ATP synthase content in the parietal cortex and hippocampus with PCI is less pronounced than with SIGM by 24% (p <0.05) and 31% (p <0.05), respectively, and than with TCI - by 53% (p <0.05) and 62% (p <0.05), respectively. Compared to the level of ATP synthase in the control group, in the 1st subgroup of SCI (the interval between dressings is 7 days), there was a decrease in the content of ATP synthase by 23 (12; 37)% in the parietal cortex (p <0 , 05) and by 7 (3; 12)% - in the hippocampus (p <0.05), in the 2nd subgroup of GSCI (the interval between dressings is 3 days), the content of ATP synthase decreased to a greater extent, amounting to 37 (27; 44)% - in the parietal cortex (p <0.05) and 26 (20; 34)% - in the hippocampus (p <0.05), and in the 3rd subgroup (the interval between dressings 1 day) there was the most significant decrease enzyme content - by 42 (35; 52)%. p <0.05 and by 33 (27; 42) %, p <0.05, respectively.
In the 3rd subgroup of GSCI (the interval between CCA dressings was 1 day), the enzyme content was less, compared with the 1st subgroup, by 27 (22; 32)% - in the parietal cortex (p <0.05) and by 18 (11 ; 23)% - in the hippocampus (p <0.05), and compared with the 2nd subgroup of GSCI - by 8 (3; 15)% in the hippocampus (p <0.05), while in the parietal cortex there were no differences was noted (p> 0.05).Thus, in the “GSCI” group, the smallest decrease in the content of ATP synthase was observed in the 1st subgroup of GSCI with an interval between dressings of 7 days, while the greatest decrease in the enzyme content was noted in the 3rd subgroup with a minimum interval between CCA dressings (1 day).

Discussion

Compared with the value in the “SCI” group, modeled by onestage ligation of both CCA, in the 3rd subgroup of SCI in both studied departments, no differences were found (p> 0.05). The content of ATP synthase in the 2nd subgroup of SCI was 17% higher than at SCI (p <0.05) in the hippocampus, while in the parietal cortex there were no differences (p> 0.05), and in 1 -th subgroup SCI - it was 30% more in the parietal cortex (p <0.05) and 34% - in the hippocampus (p <0.05) than in rats with SCI. Compared with the value in the group “PCI”, in the 1st subgroup of GSCI in both studied departments there were no differences in the content of ATP synthase (p> 0.05), in the 2nd subgroup of GSCI it was less by 18% in the parietal cortex (p <0.05) and by 20% - in the hippocampus (p <0.05), and in the 3rd subgroup of SIGM the differences from SCI were more pronounced and amounted to 26% (p <0.05) and 27% ( p <0.05), respectively. The severity of changes in the content of ATPsynthase in the 2nd and 3rd subgroups of GSCI was greater: by 18% (p <0.05) - in the hippocampus of the brain of rats of the second subgroup of SSHM and by 21% - in the parietal cortex (p <0,05) and 25% in the hippocampus (p <0.05) in the 3rd subgroup of rats with SCI. The content of ATP-synthase in the 1st subgroup of SSIGM (the interval between CCA dressings was 7 days) was the closest to the indicators in the “PCI” group, while in the 3rd subgroup of GSCI, with a minimum interval between CCA dressings of 1 day, in to a greater extent was close to the values of the enzyme content in the “SCI” group, modeled by simultaneous ligation of both CCA, which indicates a more pronounced damage to the V complex of the electron transport chain in this model of SCI.
Studies have shown the dependence of the severity of brain damage in SSHM on the interval between the cessation of blood flow in both CCA. With a 7-day interval between CCA dressings, the content of ATP synthase was restored. The results obtained agree with the previously obtained data. According to which the smallest morphological changes in neurons were noted in the “CHIGM” groups and the 1st subgroup “GSCI”, with an interval between CCA dressings of 7 days. It is obvious that with these methods of modeling IHM, adaptation processes occur that prevent the development of pronounced morphological changes and allow neurons to adapt to conditions of moderate hypoxia. So, for example, in PCI, the absence of pronounced morphological changes in rats is explained by the compensation of blood circulation in the circle of Willis. With GSCI, when the time interval (7 days between dressings) is sufficient for the development of adaptive processes, the productivity of mitochondrial respiration increases [5], and, possibly, the production of nitrogen monoxide and hypoxia-induced factor are activated [4]. Modeling of more severe types of ischemic damage leads to pronounced morphological changes in neurons in the parietal cortex and hippocampus of the rat brain - a decrease in their size, deformation of perikarya, an increase in the degree of neuronal chromatophilia with their simultaneous wrinkling and subsequent death. To the greatest extent, these disorders were expressed in the 3rd subgroup of SCI with the shortest interval between dressings, which was 1 day, and in the TCI group [4]. This, probably, can explain, in comparison with the groups “TCI”, “SCI” and the 3rd subgroup “SCI”, the higher content of ATP synthase in the cytoplasm of neurons in the 1st and 2nd subgroups “SCI” and “ PCI “.

Conclusion

Thus, the most pronounced decrease in the content of ATP synthase was observed in the groups “TCI”, “SCI” and in the 3rd subgroup “SCI”, with a minimum time interval between CCA dressings. With GSCI with an interval between CCA dressings of 7 days, the suppression of the content of ATP synthase was not so significant [20,21].

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Friday, October 28, 2022

Computational Screening for Novel Herbal-based SARS-CoV-2 Structural Protein Modulators

Computational Screening for Novel Herbal-based SARS-CoV-2 Structural Protein Modulators

Introduction

Viral diseases and their outbreaks posed threats to human health and wellness and sometimes very deadly globally. Plants have been found to be essential not only for food but also for medicine, and the metabolism of plants is found to be the source of many medicinal compounds for drug discovery. Many herbal drugs have been used in clinics for hundreds or thousands of years ones their safety and effects have been repeatedly tested and can be immediately used during emergencies. Plant-derived phytochemicals provide an excellent option for the safe treatment of infectious diseases. Several recent articles [1-5] have emphasized the importance of natural products from traditional medicine in the drug discovery process and described their continued success in contributing important molecules to the drug development pipeline. Also, antiviral herbal medicines have been used in many historical epidemics, and their analogs have been employed as the first line of defense against viral diseases. In March 2020, the COVID-19 was declared a pandemic by the World Health Organization (WHO) [6]. The virus beta coronavirus was identified to be related to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and named SARS-CoV2 [7]. The outbreak was found to be more deadly to people that have underlining chronic diseases linked to poor nutrition. The antimalarial drug Chloroquine (CHL) and its safer derivative Hydroxychloroquine (HCHL) have been proposed to be a possible treatment for SARS coronavirus- 2 (SARS- CoV- 2) , the causative agent of COVID- 19.
CHL /HCHL has anti-inflammatory activity and is used to treat rheumatoid arthritis, lupus, and osteoarthritis. However, CHL /HCHL has shown severe side effects, which may lead to heart disease [8]. Accordingly, these developments have prompted us to refocus our research on more safe and effective medications. Several kinds of essential oils and medicinal plants have been used for many centuries for the treatment of respiratory infections, asthma, dermatitis, and gastrointestinal diseases, and many studies describe antiviral activities of plant essential oils (E.O.s) [9-17]. The multiple uses of E.O.s in the flock medicine encouraged many investigators to isolate the possible active components and conduct in vivo and in vitro studies on laboratory animals and human beings, to understand its pharmacological action. These include immune stimulation, anti-inflammatory, anticancer, antimicrobial, anti-parasitic, antioxidant, antiviral, and hypoglycemic.

Materials and Methods

Ligands Preparation

The structures of the active compounds isolated from these plant species were drawn into chem draw software [18] and exported to discovery studio (Figures 1-3). Ligands were prepared by adding hydrogens to all compounds, after which energy minimization was performed using the MMFF94x force field. Furthermore, ligand geometries were optimized using a Root Mean Square (RMS) gradient of 0.05 kcal/mol/Ã… using Discovery Studio 2020 [19].

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Figure 1: Active compounds in Artemisia annua.

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Figure 2: Active compounds in Zingiber officinale.

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Figure 3: Active compounds in Hibiscus sabdariffa.

Protein Preparation

The crystal structure of Sars-Cov-2 protease and spike protein were downloaded from the Protein Data Bank (PDB), using the PDB ID ‘6LU7’ for protease and ‘6M0J’ for spike protein respectively. The protein was then cleaned and extra chain with water molecules were removed. Minimization of the protein complex, to remove any constrain in the structure, was completed using prepare protein option in the software. Binding site was then generated, and ligands were docked using the C Docker [19].

Molecular Docking Studies to Illustrate the Importance of Plants in Treatment of Sars-Cov-2

To illustrate the importance of these plants, the active compounds isolated from these plants in the literature was used to study their possible effects in the current Sars-Cov-2 virus outbreak. Active compounds derived from these plants are illustrated in Figures 1-3. Molecular docking studies were implied to study the interaction of the most active compounds present in these three plant species and the important receptors of Sars-Cov-2 virus. Docking studies were performed using BIOVIA Discovery studio 2020 [19]. Crystal structure of Sars-Cov-2 protease and spike protein attached to the ACE2 receptor is available in Protein Data Bank (PDB) [20].

Validation of the Docking Results

The docking experiments were validated by redocking of the co-crystal structure. The crystal structure of Sars-Cov-2 protease is present with the co-crystal structure. This co-crystal structure was used to build the binding site pocket. The co-crystal structure was then re-docked, to validate the results, with 10 posses. First five docking poses were selected and RMSD was calculate for each configuration. RMSD value was < 2 Ã… which is acceptable and indicate the validity of the prepared protein complex and docking protocol. The crystal structure of spike protein of Sars-Cov-2 is bound with ACE2 receptor (ACE2 receptor is used by the virus to enter the host cell). The ACE2 protein was removed, and spike protein was refined to build any missing loops. Binding site on the spike protein was then identified using the receptor cavities and the top binding site was selected for further docking (Figure 4). The prepared ligands were then docked in the prepared protein using the CDOCKER protocol with 10 poses of each ligand and pose cluster radius of 0.5 Ã…. CHARM m-based molecular dynamics algorithm is used by the CDOCKER tool to dock the ligand into the receptor protein and compute the interaction energies of the ligands. The interaction of the amino acids to the ligand was then viewed and saved in publication quality.

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Figure 4: A; Spike protein and its active site determined by receptor cavity, B; interactive amino acids in the active site of spike protein.

Docking of Active Compounds in ACE2 Receptor Protein

Since the first outbreak of MERS in 2003 and the present Sars- Cov-2 outbreak in 2019, the coronavirus family have evolved and have become more dangerous and contagious. Another report published showed the evolution of current Sars-Cov-2 virus, suggesting a more severe second wave in the future. Most of the viruses belong to Coronavirus family use ACE2 receptor in the humans to enter the host cell. Although the evolution of virus protease and spike protein, these viruses use the same ACE2 receptor to gain host cell entry. ACE2 receptor being the target receptor to enter the host cell by the virus posit a viable target to stop the spread of Sars-Cov-2. Inhibiting ACE2 receptor will stop the viral entry into the host cell and replication. We used the crystal structure of ACE2 receptor protein bound with the Sars-Cov-2 spike protein (PDB ID 6M0J). The spike protein was removed and ACE2 receptor protein was refined to build any missing loops. Blind docking was then used to dock the most active compounds from the plant species to ACE2 receptor protein.

Results and Discussion

Table 1 describes the active compounds of the plant species with the CDOCKER interaction energies on the three different targets of Sars-Cov-2 virus. Higher values showed more interaction between the ligand and the amino acid of the target protein. The results showed that Oleanene 1 active compound of plant Hibiscus sabdariffa showed good interaction energy with protease enzyme of the coronavirus as compared to other active compounds of these plants. Oleanene 1 formed good interaction with amino acid THR25, THR26, PRO168 and GLY166 of the binding pocket. Similar hydrogen bond interaction with GLY166 and the co-crystal ligand was also seen. Figure 5 showed the compound Oleanene 1 fits perfectly within the binding pocket of Sars-Cov-2 protease binding site. Myreceric acid of the same species (Hibiscus sabdariffa) showed good interaction energy when docked in the Sars-Cov-2 spike protein. Inhibition of spike protein will halt the attachment of the virus into the host cell. Myreceric acid forms conventional hydrogen bond with amino acid ILE468, SER469, ARG454 and GLU471, Pi-bond with ASP467 and carbon-hydrogen bond with ARG457 amino acid (Figure 6). As discussed above, ACE2 receptor in the human is a viable target to stop the entry of virus into the host cell.

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Figure 5: Compound Oleanene 1 (Hibiscus sabdariffa) in the active site of Sars-Cov-2 protease enzyme.

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Figure 6: Compound Myreceric acid (Hibiscus sabdariffa) in the active site of Sars-Cov-2 spike protein.

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Table 1: Active compounds of the plant species with CDOCKER interaction energy.

The docking results of the most active compounds of the three plant species with the ACE2 receptor protein showed that 6-Gingerol of plant Zingiber officinale possess good interaction energy with ACE2 receptor active site. Figure 7 showed the 6-gingerol in the active site of ACE2 receptor protein. 6-Gingerol showed hydrogen bond interaction with amino acid GLU398, ARG514, TYR515 and ARG273 of the active site. The docking results shows that Hibiscus sabdariffa plant is promising in killing the Sars-Cov-2 virus, as the active compounds of this plant showed good interaction energy with virus protease and spike protein. However, Zingiber officinale showed promising results to alter the entry of virus into the host cell by interacting with ACE2 receptor protein Table 1.

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Figure 7: Compound 6-Gingerol (Zingiber officinale) in the active site of ACE2 receptor protein.

Conclusion

In conclusion, the study conducted showed that myreceric acid found in Hibiscus sabdariffa is effective in binding the active site of SARS-CoV-2 spike protein. Similarly, Oleanene1 extracted from the same species effectively binds to the SARS-CoV-2 protease. Since both the active compounds were found in Hibiscus sabdariffa, the use of this plant species to probe its effectiveness in the current SARS-CoV-2 outbreak should be further studied.

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Neurological Manifestations of COVID-19: A Brief Update on the Cuban Context

  Neurological Manifestations of COVID-19: A Brief Update on the Cuban Context Introduction Despite of severe acute respiratory syndrome cor...