It is time that universities reexamine what is meant by globalization. Contemporary researchers in science and the humanities (Critchley, Chomsky, Mumford, Ostrom, Eisenstein, Ferry, Orr, Shiva, Klein, Margulis, Meadows, Capra and Tolba, just to name a few) have aptly redefined the concept of « world » as a biological and cultural ecosystem. This paper seeks ways to integrate the theory and practice of eco-citizenship into various cross-disciplinary aspects of higher education, with a focus on curricular adjustments that may be steered by World Languages and Cultures programs. While "global citizenship" is still often understood today as a form of supranational citizenship that may find its actualization through the valuable, yet often arrested efforts of the United Nations, or as the individualistic result of a neoliberal economic emancipation of markets and capital throughout the world, this notion must rather be embedded within a radically cultural, natural and ethical bedrock from which a more potent world citizenry will stem. Departments of World Languages and Cultures and cultures are ideally positioned in the academic landscape to foster the development of a greater eco-civic and biospheric awareness that can permeate new curricular orientations of universities in the US and abroad.

Cognitive scientists have paid very little attention to magic as a distinctly human activity capable of creating situations or events that are considered impossible because they violate expectations and conclude with the apparent transgression of well-established cognitive and natural laws. And even though magic techniques appeal to all known cognitive processes from sensing, attention and perception to memory and decision making, the relation between science and magic has so far been mostly unidirectional, with the primary goal of unraveling how magic works. Building up from the deconstruction of a classic magic trick, we provide here a cognitive foundation for the use of magic as a unique and largely untapped research tool to dissect cognitive processes in tasks arguably more natural than those usually exploited in artificial laboratory settings. Magicians can submerge every spectator into the precise experimental protocol they have previously designed, accounting with ease for both circumstantial and social contexts. Magicians do not base the success of their experiments in statistical measures that smear out the individual in favor of an average spectator that we know never exists in the real world. They target each and everyone in the audience and, often, with a complete accomplishment. Magicians deliver their cognitive manipulations in real-time, in tight closed-loop with the audience, and in a single trial (they cannot afford to repeat the trick if it fails). Magic has also an inherent and strong social component, merging the private cognitive processes of each spectator with the group dynamics. Finally, when combined with the wide range of precise measuring and wearable technologies available today, magic paves the way for a road not taken towards real-world cognitive science. We dare to speculate that some of the mysteries of how the brain works may be trapped in the split realities present in each magic effect.

Advances in cosmology and astronomical observations over the last two decades have revealed significant tensions and many ambiguities within the standard model of cosmology of a spatially flat Universe, the lambda cold dark matter model. Moreover, the recent Planck Legacy 2018 (PL18) release has confirmed the presence of an enhanced lensing amplitude in the cosmic microwave background (CMB) power spectra, which prefers a positively curved early Universe with a confidence level higher than 99%. This paper addresses the study of a quantum mechanism that could replace the concept of dark matter and energy by considering a primordial curvature as preferred by the PL18 release while yielding the present-day spatial flatness. The implied primordial curvature is incorporated as the background curvature to extend the field equations in terms of the brane-world modified gravity. The Universe evolution is modelled by utilizing a new wavefunction of the Universe that propagates in the bulk with reference to the scale factor of the early Universe and its radius of curvature upon the emission of the CMB, which revealed both positive and negative solutions. This characteristic implies that a pair of entangled wavefunctions was created and evolved in opposite directions as a manifestation of distinct matter and antimatter sides of the Universe. The wavefunction indicates a nascent hyperbolic expansion away from early energy is followed by a first phase of decelerating expansion during the first 10 Gyr, and then, a second phase of accelerating expansion in reverse directions, whereby both sides free-fall towards each other under gravitational acceleration. The predicted background curvature evolution demonstrates the fast orbital speed of outer stars owing to external fields exerted on galaxies as they travelled through earlier conformally curved spacetime. Finally, the wavefunction predicts an eventual phase of rapid spatial contraction that culminates in a Big Crunch, signaling a cyclic Universe. These findings reveal that early plasma could be separated and evolved into distinct sides of the Universe that collectively and geometrically inducing its evolution, physically explaining the effects attributed to dark matter and energy.

Most traditional theories of intelligence have little to do with the question of whether people with high intelligence can successfully address real world problems. A high IQ is correlated with many important outcomes (e.g., academic prominence, reduced crime), but it does not protect against cognitive biases, partisan thinking, reactance, confirmation bias, and even falling for discredited beliefs such as alchemy, cold fusion, and astrology. There are several newer theories that directly address the question about solving real-world problems. Prominent among them is Sternberg’s adaptive intelligence with “adaptation to the environment” as the central premise, a construct that does not exist on standardized IQ tests (e.g., Sternberg, 2019). Similarly, Stanovich and West (2014) argue that standardized tests of intelligence are not measures of rational thought—the sort of skill/ability that would be needed to address complex real-world problems. Halpern and Butler (2020) advocate for critical thinking as a better model of intelligence for addressing real-world problems than those that are based on psychometric properties of general intelligence. Yes, intelligence (i.e., critical thinking) can be enhanced and used for solving a real-world problem like Covid-19, which we use as an example of contemporary problems that need a new approach. Critical thinking may be an antidote for the chaos of the modern world.

George Satayana stated that “those who do not learn from history are doomed to repeat it”. As our UK “good outcome” death toll of 20,000 from coronavirus (SARS CoV -2/ COVID -19) in 2020 has sadly been surpassed; never has a phrase been more pertinent. The last major pandemic on a similar scale to COVID-19 is “Spanish Flu” from 1918. We aim to delineate the timeline of events in response to the 1918 Spanish flu pandemic and compare this to the timeline of COVID 19 response, given that the NHS and WHO have since both been long established. In the last 102 years many changes have occurred. Health services across the world have significantly improved, with the advent of mechanical ventilation and antimicrobial treatments. Vaccination programmes against common pathogens have prevented many large-scale disease threats, however novel illnesses have also emerged. Worldwide communication through the Internet and many agencies including the World Health Organisation has improved, and the awareness and surveillance of disease is more prominent. Despite advances in healthcare and communication, the national and international timeline for public health intervention in the current COVID pandemic in comparison to the Spanish flu pandemic of more than 100 years ago is virtually identical. The World Health Organisation operates to promote global health and prevent spread of disease, with this in mind; should the WHO have intervened earlier?​ We need to learn quickly from this pandemic and improve planning for the future.

Real-world evidence (RWE) is increasingly involved in the early benefit assessment of medicinal drugs. It is expected that RWE will help to speed up approval processes comparable to RWE developments in vaccine research during the COVID-19 pandemic. Definitions of RWE are diverse marking the highly fluid status in this field. So far, RWE comprises information produced from data routinely collected on patient’s health status and/or delivery of health care from various sources other than traditional clinical trials. These sources can include electronic health records, claims, patient-generated data including in home-use settings, data from mobile devices as well as patient, product and disease registries. The aim of the present update was to review the current RWE developments and guidelines mainly in the U.S., the UK, Europe and Germany field during the last decade. RWE has already been included in various approval procedures of regulatory authorities reflecting its actual acceptance and growing importance in evaluating and accelerating new therapies. However, since the RWE research is still in a transition process and since a number of gaps in this field have been explored, more guidance and a consented definition are necessary to increase the implementation of real-world data.

Background: Objectives were to determine the real-life effectiveness and safety of DT with dolutegravir (50 mg/QD) plus lamivudine (300 mg/QD) in multiple-tablet regimen (MTR) in naïve PLHIV followed up for 48 weeks and to evaluate the compliance and satisfaction of patients. Material and methods: Open, single-arm, multicenter, non-randomized clinical trial from May 2019 through September 2020 with 48-week follow-up. Results: The study included 88 PLHIV (91% male) with mean age of 35.9 years; 76.1% were MSM. Mean baseline CD4 was 516.4 cells/uL, with viral load (VL) of 104,828 cop/mL, and 11.4% were in AIDS stage. DT started within 7 days of first specialist consultation in all patients and the same day in 84.1%; 3.4% had baseline resistance mutations (K103N, V106I+E138A, and V108I); 12.5% were lost to follow-up. At week 48, 86.3% had VL< 50 cop/uL by intention-to-treat analysis and 98.7% by per-protocol (PP) analysis. Virological failure (VF) was recorded in 1.1%, with no resistance mutation. One blip was detected in 5.2%, without VF. Three reported anxiety, dizziness, and cephalgia, respectively, at week 4 and one insomnia at week 24; none reported adverse events at week 48. Mean weight was 4 kg higher at 48 weeks (p=0.0001) and abdominal circumference 3 cm larger at 24 weeks (p=0.022). No forgetfulness occurred in 98.7% of patients. Patient satisfaction was 90/100 at 4, 24, and 48 weeks. Conclusion: Real-world data demonstrate that dolutegravir plus lamivudine in MTR is effective, safe, and satisfactory, moderately increasing weight and abdominal circumference and administrable on a test-and-treat strategy.

The following guide is aimed at aiding in the curation of herbarium collections in Melastomataceae, with an emphasis on the New World species. It contains a summary of the taxonomic realignments at the tribal and generic level within Neotropical taxa of Melastomataceae, as well as some general comments for other groups. A table with a generic linear sequence is also provided, as well as tables with new and synonymized New World genera since 2005 and all currently accepted species. Lastly, a table with the synonyms of over 1000 accepted Neotropical species that have been impacted by these generic realignments is also provided.

Current cellular facts allow us to follow the link from chemical to biochemical metabolites, from the ancient to the modern world. In this context, the "RNA world" hypothesis proposes that early in the evolution of life, the ribozyme was responsible for the storage and transfer of genetic information and for the catalysis of biochemical reactions. Accordingly, the hammerhead ribozyme (HHR) and the hairpin ribozyme, belong to a family of endonucleolytic RNAs performing self-cleavage that might occur during replication. Furthermore, regarding the ultraconserved occurrence of HHR in several genomes of modern organisms (from mammals to small parasites and elsewhere), these small ribozymes have been regarded as living fossils of a primitive RNA world. They fold into 3D structures that generally require long-range intramolecular interactions to adopt the catalytically active conformation under specific physicochemical conditions. By studying viroids as plausible remains of ancient RNA, we recently demonstrated that they replicate in non-specific hosts, emphasizing their adaptability to different environments, which enhanced their survival probability over the ages. All these results exemplify ubiquitously features of life. Those are the versatility and efficiency of small RNAs, viroids and ribozymes, as well as their diversity and adaptability to various extreme conditions. All these traits must have originated in early life to generate novel RNA populations.

In the world city theory, most researchers focus on the service sector in the urban economy and less discuss the role of manufacturing. However, the path of only emphasizing financial and corporate service could not fit the sustainability concept. Compared to Anglo-American world city, Global South’s world cities have distinct pathway to be industrialization, tertiarization and globalization. This paper adopted dynamic historic perspective with first-hand materials including in-depth interviews with managers and government officers and second-hand data including yearbook statics and economic census to closely examine the emerging world city-- ‘World Factory’ in Global South, Guangzhou in China, from 1949 to 2015, to emphasize how manufacturing affects the urban globalization through three dimensions, economic, social and spatial dimensions. To make the confirmation of the role of manufacturing in Guangzhou as sustainable world city, we find manufacturing in Guangzhou builds up the basic foundation of export-oriented economy and makes positive effects on urban economic transformation. In addition, manufacturing remains important source of employment and foreign immigration. Along with urbanization and industrialization, urban spatial expansion and aggregation changes with different urban development concept. We provide new insights on multiple globalization on manufacturing for sustainable world city.

Considerable efforts have been devoted to modifying gravity, which aim to elucidate the possible existence or nature of dark matter and energy, describe observational data more effectively, and formulate quantum gravity. In addition, despite the immense success of the quantum field theory, the framework requires renormalization techniques and breaks down at high energies. Recently, the Planck legacy 2018 release has confirmed the existence of an enhanced lensing amplitude in the cosmic microwave background power spectra, which prefers a positively curved early Universe with a confidence level higher than 99%. This study considers the implied curvature of the early Universe as the curvature of “the background or 4D conformal bulk as a manifestation of vacuum energy” and distinguishes it from the localized curvature that is induced in the bulk by the presence of celestial objects that are regarded as ”4D relativistic cloud-worlds.” Analogously, because gravity appears to emerge owing to spacetime curvature and does not exhibit critical characteristics shared by other fields, it has been incorporated as the local curvature of the bulk affecting the embedded quantum fields that are regarded as propagating “4D relativistic quantum clouds.” To consider the effects of the bulk on embedded clouds, this paper presents interaction field equations in terms of brane-world modified gravity and the perspective of geometrization of the quantum mechanics wherein gravity is manifested by the curvature of 4D conformal bulk as an indicator of the field strength of vacuum energy on the embedded 4D relativistic clouds in addition to the boundary interactions, which could remove the singularities and satisfy a conformal invariance theory. A visualization of the evolution of the 4D relativistic cloud-worlds over the conformal spacetime of the 4D bulk is presented, whereas the standard said theories can be recovered from the interaction field equations.

The provenance of the aminoacyl-tRNA synthetases (aaRS) poses challenging questions because of their role in the emergence and evolution of genetic coding. We investigate evidence about their ancestry from curated structure-based multiple sequence alignments of a structurally invariant “scaffold” shared by all 10 canonical Class I aaRS. Three uncorrelated phylogenetic metrics—residue-by-residue conservation, its variance, and row-by-row cladistic congruence—imply that the Class I scaffold is a mosaic assembled from distinct, successive genetic sources. These data are especially significant in light of: (i) experimental fragmentations of the Class I scaffold into three partitions that retain catalytic activities in proportion to their length; and (ii) evidence that two of these partitions arose from an ancestral Class I aaRS gene encoding a Class II ancestor in frame on the opposite strand. Phylogenetic metrics of different modules vary in accordance with their presumed functionality. A 46-residue Class I “protozyme” roots the Class I molecular tree prior to the adaptive radiation of the Rossmann dinucleotide binding fold that refined substrate discrimination. Such rooting is consistent with near simultaneous emergence of genetic coding and the origin of the proteome, resolving a conundrum posed by previous inferences that Class I aaRS evolved long after the genetic code had been implemented in an RNA world. Further, pinpointing discontinuous enhancements of aaRS fidelity establishes a timeline for the growth of coding from a binary amino acid alphabet.

This paper analyzes the political and economic changes in the world after the drastic changes in eastern Europe, starting with Chinese President Xi Jinping's viewpoint "the biggest change in a century". Also, the new international situation and new development in the post-epidemic as well as the development path and direction of China in the post-epidemicera are expected.

The origin of life has not been solved as yet, in spit of the time passage more than thirty years from publication of RNA world hypothesis by W. Gilbert (1986), which is based on the “gene/replicator--first” theory. On the contrary, I have proposed [GADV]-protein world hypothesis (GADV hypothesis), assuming that life emerged from [GADV]-protein world, which is grounded on the “protein/metabolism-first” theory. However, two weak points of protein world hypothesis, (i) protein cannot be produced without gene, and (ii) protein cannot be self-replicated, have been frequently pointed out by supporters of RNA world hypothesis. Then, I examined whether the two weak points could be overcome by GADV hypothesis or not. From the results, it was confirmed that (i) [GADV]-protein could be pseudo-replicated in the absence of gene owing to protein 0^th-order structure or [GADV]-amino acids, and (ii) the replication ability is not always required from the beginning but it is sufficient to acquire it at some time point until the emergence of life. Thus, it was concluded that life emerged as [GADV]-protein world hypothesis, which is grounded on the “protein/metabolism-first” theory, expects.

With its sights set on sustainable development, transport policy finds itself confronted with the challenge of convincing people to abandon the current path of growth and instead use small, slower vehicles with a reduced range in the future. The problem with this goal is that people's mental structures are shaped by the car ensconced in their heads. Thinking in other terms hardly seems possible; moreover, many of the products classified as vehicles, but smaller in scale than the "car" and that already exist, remain unknown, nor can they be tried out - they are quite literally nowhere to be seen. In light of this situation, the German Federal Environmental Foundation has commissioned a feasibility study to explore the establishment of a World of Experience (Erlebniswelt) of sustainable urban mobility - the EcoMobileum®. Here, the aim is to open up the horizons of a new culture of mobility in order to get people excited about the transformation of mobility.

In recent years, the role of non-coding RNAs (ncRNAs) in regulating cell physiology has begun to be better understood. Recent discoveries in viral molecular biology have revealed that such cellular functions are disturbed during viral infections mainly due to host cell ncRNAs, cellular factors, and virus-derived ncRNAs. Apart from the interplay between those molecules, other interactions derive from the specific folding of RNA virus genomes. These fulfill canonical regulation functions such as replication, translation, and viral packaging. In some cases, folds serve as precursors of small viral RNAs whose biogenesis is not yet clearly understood. Since ncRNAs and RNA viral genomes modulate complex molecular and cellular processes in viral infections, a new taxonomy is being proposed here overarching three main categories, considering the current information about ncRNA interactions in some well-known viral infections. The first category shows examples of host ncRNAs associated with the trigger of the immune response under viral infections. The second category describes interactions between the virus and host ncRNAs. The last category shows how the shape of the RNA viral genome is essential in processing RNAs derived from viruses. Finally, we introduce evidence of how these three categories can also work as a framework in order to organize known interactions of ncRNAs and cellular factors under DENV infection. This new taxonomy of interactions provides a comprehensive framework for organizing the ncRNA regulatory roles in the context of viral interactions and an RNA world.

Simian endogenous retrovirus, SERV, is a successful germ line invader restricted to Old World monkey (OWM) species. (1) Background: The availability of high quality primate genomes warrants a study of the characteristics, evolution and distribution of SERV proviruses; (2) Methods: Cercopithecinae OWM genomes from public databases were queried for the presence of full length SERV proviruses. A dataset of 81 Cer-SERV genomes was generated and analyzed; (3) Results: Full length Cer-SERV proviruses were mainly found in terrestrial OWM, and less so in arboreal, forest- dwelling monkeys. Phylogenetic analysis confirmed the existence of two genotypes, Cer-SERV-1 and Cer-SERV-2, with Cer-SERV-1 showing evidence of recent germ line expansions. Long Terminal Repeat (LTR) variation indicated that most proviruses were of a similar age, and were estimated to be between &lt;0.3 and 10 million years old. Integrations shared between species were relatively rare. Sequence analysis further showed extensive CpG methylation-associated mutation, variable Primer Binding Site (PBS) use with Cer-SERV-1 using PBSlys3 and Cer-SERV-2 using PBSlys1,2, and the recent gain of LTR motifs for transcription factors active during embryogenesis in Cer-SERV-1; (4) Conclusions: sequence analysis of 81 SERV proviruses from Cercopithecinae OWM genomes provides evidence for the adaptation of this retrovirus to germ line reproduction.

Fruits play an important role in human diet and to maintain better health. Globally, India ranks second in fruits production after China. Grapes, mangoes, bananas and oranges were the selected fruit crops for study purpose. The study period is from 1990 to 2018. The present study analyzed the growth rates, instability and elasticity of export quantity, prices of selected fruit crops from major producing countries in the world and also dealt with the major export destinations of Indian fruits. The results showed that an exporting countries should export grapes to Peru, Spain and Chile; bananas to the Panama, Philippines and Ecuador; mangoes to Italy, Egypt and Australia; and, oranges to Thailand, Philippines and Mexico for generating higher revenue because in global market those countries were associated with highest export price with the stability. Globally, the export price elasticity was inelastic in all countries of grapes, oranges and bananas except Italy in oranges and panama in bananas. The study found that export price elasticity of mangoes was marginally higher in the Spain and the Netherlands. The study showed that the major destinations for Indian fruits are; USA, Germany and Netherlands for grapes; USA, Belgium and Germany for bananas; USA, the Netherlands and Viet Nam for mangoes; and, Germany, France and Netherlands for oranges. Globally, the current study gave useful data to comprehend competition of prices for fruits to importing countries. This study may assist in preparing major price strategies and policies on fruits and also assisted in foreign earnings for all nations.

As Christopher Alexander conceived and defined through his life’s work – The Nature of Order – wholeness is a recursive structure that recurs in space and matter and is reflected in human minds and cognition. Based on the definition of wholeness, a mathematical model of wholeness, together with its topological representation, has been developed, and it is able to address not only why a structure is beautiful, but also how much beauty the structure has. Given the circumstance, this paper is attempted to argue for the wholeness as the scientific foundation of sustainable urban design and planning, with the help of the mathematical model and topological representation. We start by introducing the wholeness as a mathematical structure of physical space that pervasively exists in our surroundings, along with two fundamental laws – scaling law and Tobler’s law – that underlie the 15 properties for characterizing and making living structures. We argue that urban design and planning can be considered to be wholeness-extending processes, guided by two design principles of differentiation and adaptation, to transform a space – in a piecemeal fashion – into a living or more living structure. We further discuss several other urban design theories and how they can be justified by and placed within the theory of wholeness. With the wholeness as the scientific foundation, urban design can turn into a rigorous science with creation of living structures as the primary aim.

In this paper, we propose two novel methods for robot-world/hand-eye calibration and provide a comparative analysis against six state-of-the-art methods. We examine the calibration problem from two alternative geometrical interpretations, called hand-eye and robot-world-hand-eye, respectively. The study analyses the effects of specifying the objective function as pose error or reprojection error minimization problem. We provide three real and three simulated datasets with rendered images as part of the study. In addition, we propose a robotic arm error modeling approach to be used along with the simulated datasets for generating a realistic response. The tests on simulated data are performed in both ideal cases and with pseudo-realistic robotic arm pose and visual noise. Our methods show significant improvement and robustness on many metrics in various scenarios compared to state-of-the-art methods.

A dogma is normally considered as a principle or a belief accepted as an indisputable truth by some individuals and/or groups. Theoretically there can be no dogmas in science, but it has been demonstrated that scientific thought operates by conceptual changes. A dogma therefore can be understood as a concept present at the heart of some contemporary research programmes that need to be altered to overcome paradigms. Here we argue that two ideas relating to emergence of the biological system research need to be re-evaluated. First, is the idea that research programmes about the emergence of the biological system are the same as those of the origin of cells. Cells are strikingly important biological entities, hard core concepts for the entire field of biology. The emergence of the biological system happened much earlier than the origin of cells and thus the First Universal Common Ancestor (FUCA) should be viewed as a great-grandfather to the Last Universal Cellular Ancestor (LUCA); i.e. the latter is the first cellular life form. Second, RNA-world theories are the focus of mainstream research programmes for the origin of life stricto sensu. In the RNA-world view, self-replication of nucleic acids is seen as one of the most relevant events in the pre-biotic world. Without denying the relevance of self-replication, we argue here that the most germane event which occurred in the pre-biotic world was the crosstalk between nucleic acids and peptides. When these two macromolecules started to interact, the singularity that aggregated the complexity required to produce life emerged. Thus, comprehension of the early origins of the translation machinery and the assembly of the genetic code is key. Therefore, the relevance of cell theory and self-replication should be re-evaluated as well as the concept of life itself.

The recognition of a place as a World Heritage Site (WHS) by UNESCO is fundamental to preserve its historical and artistic inheritance and, at the same time, to encourage visits to that area. The purpose of this article is to contribute to the study of the relationship between WHS and cultural tourism, with a marked sustainable character, through the presentation of the results of research conducted in the city of Cordoba (Spain) and which analyses the sociodemographic profile of the tourists, the variables that influence their level of satisfaction and of their loyalty and the classification of the travelers through different variables. The principal results of the research show the significant educational level of the surveyed tourists, as well as the high level of satisfaction with the visit, the high number of countries of origin and the outstanding motivation for knowing the city’s heritage roots.

The central dogma of molecular biology dictates that, with only a few exceptions, information proceeds from DNA to protein through an RNA intermediate. Examining the enigmatic steps from prebiotic to biological chemistry, we take another road suggesting that primordial peptides acted as template for the self-assembly of the first nucleic acids polymers. Arguing in favour of a sort of archaic “reverse translation” from proteins to RNA, our basic premise is a Hadean Hearth where key biomolecules such as amino acids, polypeptides, purines, pyrimidines, nucleosides and nucleotides were available under different prebiotically plausible conditions, including meteorites delivery, shallow ponds and hydrothermal vents scenarios. Supporting a protein-first scenario alternative to the RNA world hypothesis, we propose the primeval occurrence of short peptides termed “selective amino acid- and nucleotide-matching oligopeptides” (henceforward SANMAOs) that noncovalently bind at the same time the polymerized amino acids and the single nucleotides dispersed in the prebiotic milieu. We describe the chemical features of this hypothetical oligopeptide, its biological plausibility and its virtues from an evolutionary perspective. We provide a theoretical example of SANMAO’s selective pairing between amino acids and nucleosides, simulating a poly-Glycine peptide that acts as a template to build a purinic chain corresponding to the glycine’s extant triplet codon GGG. Further, we discuss how SANMAO might have endorsed the formation of low-fidelity RNA’s polymerized strains, well before the appearance of the accurate genetic material’s transmission ensured by the current translation apparatus.

A reliable and affordable energy supply is a fundamental prerequisite for reducing poverty, promoting investment, and boosting economic growth in the developing world. Among the different challenges that developing countries face, chronic energy crises are harrowing. The crises result from the unsatisfactory state of the central grid, a misguided energy mix, and ill-informed policies, among other things. The possibility of solving energy crises through a variety of alternative solutions is worth exploring. This review discusses two paths of energy development side by side: a traditional “hard” path of energy development (i.e., central grid extension powered by fossil fuels and nuclear energy expansion) and a relatively recent “soft” path of energy development, which is based on energy conservation and the deployment of renewable energy resources. This paper focuses on one central axis of the discussion: centralization vs. decentralization. This discussion, in turn, has technological, economic/business, and political dimensions. Finally, the paper discusses the significance of the debate from meeting the developing world’s energy demands. The paper intends not to prefer one or another path of energy development, nor it gives recommendations on diffusing or adopting those development paths. Instead, it explores the literature’s central arguments that might help frame the questions for further research. While this debate could be used to ask interesting questions that might help solve the energy crisis in the developing world, the discussion informs countries to advance policies specific to their circumstances under the umbrella of a sound and thoughtful energy productivity policy framework.

In situations of uncertainty, scenarios serve as input for evidence-based decision making. However, past experience shows that not all scenarios are treated equally, and we hypothise that only those based ion a world view shared by decision makers are perceived as credible and receive full attention. While intuitively plausible, this hypothesis has not been analysed by quantitative correlation analyses, so instead of drawing on quantitative data the paper analyses the archetypical scenarios developed in the ALARM project to substantiate the plausibility by a comparative analysis of world views, value systems and policy orientations. Shock scenarios are identified as a means to explore the possibility space of future developments beyond the linear developments models and most scenario storylines suggest. The analysis shows that the typical scenarios are based on mutually exclusive assumptions. In conclusion, a comparison of storyline and empirical data can reveal misperceptions, policy failures and the need to rethink world views as a necessary step to open up to new challenges. Deeply held beliefs will make this a transition unlikely to happen without severs crises, if not dedicated efforts to reveal the role of world views for scenarios and policies are undertaken.

Currently there is little doubt left on the symbiogenetic nature of eukaryotes - genomes of archaeon and bacterium participated in shaping a genome of last eukaryotic common ancestor in equal albeit asymmetric manner, while a merger event itself indicated the advent of a new domain of life. The “symbiogenetic” framework of interaction of two partners is proposed, outlining similar steps essential for three major advents: the origin of life, the origin of complex life and the origin of humans. Given the immense importance of proper energy source for the evolution of life it seems plausible that for any principal increase in complexity, a partnership with a novel energy donor is required. Moreover, a “language” elaborated in the course of communication of partners might have been a prerequisite for a subsequent increase in complexity. Transitions, which led to RNA-protein world, eukaryotes and human brain, resulted in advent of complex languages via communication onsets between two entities in close partnership. Accordingly this further facilitated formation of first cells, multicellular organisms and human society.

All life on Earth uses three integrated molecular systems in which genetic information contained in DNA base sequences is transmitted to ribosomes by RNA and a genetic code, then translated into the amino acid sequences of structural and catalytic proteins. Therefore, the most important point for understanding the origin of life is to determine how such systems could emerge from random processes on the early Earth. In this review, two alternatives are compared: the RNA world hypothesis and the [GADV]-protein world hypothesis. [GADV] refers to four amino acids, Gly [G], Ala [A], Asp [D] and Val [V] that are conserved in the amino acid sequences of many common proteins. Here I will argue that the origins of the three primary processes required for life to begin can be better explained by the GADV hypothesis than the RNA world hypothesis. The GADV hypothesis also incorporates a conversion process by which random polymers can evolve into proteins with ordered sequences.

With the development of society and the economy, the unified planning of architectural style has become a difficult problem in the competition between urban expansion and the protection of tra-ditional buildings in villages and towns. At the same time, it also allows people to re-examine the appearance and quality of life of traditional village buildings. In this paper, the Conditional Gen-erative Adversarial Network (CGAN) is used to construct a method of building facade generation in villages and towns, so as to gradually realize the governance of the style of villages and towns. At the same time, it has also reduced the restoration of the facades of villages and towns and the graphic design of rural tourism products, showing its application value and potential in the field of planning and design. In the research, taking villages and towns in the Wuyishan area of China as an example, the method is used to carry out model training, image generation, and comparison of the derivation results of different assumed building contours and product contours. The research shows that: (1) CGAN can be used to derive and design the facades of conventional civil buildings in villages and towns. (2) In terms of product graphic design, especially the common tourist cultural products fans and water cups, show significant potential. (3) The construction of this method is not only applicable to villages and towns under the World Heritage City, but can be further promoted and used in the future for cities and villages that have a demand for architectural style consistency.

This article investigates the dynamics of socio-ecological systems (SESs) unsustainability. By adopting a theoretical standpoint grounded in systems’ theory, the analysis shows how SESs’ teleology (or final cause) is of the utmost relevance for understanding unsustainability and how it is pivotal for envisioning possible evolutionary trajectories towards sustainability. Building on the contributions of both system and social scientists, the study argues that SES’s teleology is determined by dominant social ontologies that require a dialectical lens to be properly dealt with. The article therefore proposes the adoption of the adaptive cycle heuristic complemented by an historical-geographical approach based on world-ecology theory as a means to dynamically model of SESs’ behaviour. Such a perspective allows for the direct comparison between the four stages of the panarchy cycle (reorganization, exploitation, conservation, and release) and the four stages theorized by the world-ecology dialectics (expansion, appropriation, capitalization, crisis). In conclusion, the article claims that both system and social scientists would benefit from including in their analysis concepts and definitions from the other field, since both provide valuable insights about SESs' processes of change and both are necessary to envision transition pathways towards sustainability.

Acute myeloid leukemia (AML) is a hematological malignancy that predominantly affects the elderly. Prognosis declines with age. For those who cannot tolerate intensive chemotherapy, historically established treatment options have been hypomethylating agents (HMAs), low dose cytarabine (LDAC), and best supportive care (BSC). As the standard of care evolves for those unfit for intensive chemotherapy, there is a need to understand established treatment pathways, clinical outcomes and healthcare resource utilization in Canada. The CURRENT study was a retrospective chart review of AML patients not eligible for intensive chemotherapy who initiated first-line treatment between 1 January 2015 and 31 December 2018. Data were collected from 170 Canadian patients treated at six hematology centers, of whom 118 received systemic therapy and 52 received BSC as first-line treatment. Median overall survival was 8.58 months and varied from 2.96 months for BSC to 13.31 months for HMAs. Over 80% of patients had at least one outpatient visit, and 67% of patients receiving systemic therapy and 71% of those receiving BSC had at least one admission to hospital, during their first line of therapy. A total of 96 (81.4%) patients receiving first line systemic therapy and 39 (75.0%) of those receiving first line BSC had at least one red blood cell or platelet transfusion. These findings highlight the unmet need for novel therapies for patients ineligible for intensive chemotherapy.

We report a prebiotically relevant solution to the N1-ribosylation of pyrimidine nucleobases, a well-known challenge in the RNA World hypothesis. It is found that the presence of metal cations and clay mineral enables the previously unachievable direct ribosylation of uracil, providing by far the highest yield. Spectroscopy and chromatography analyses confirmed the formation of ribosylated uracil. The method can also be extended to the ribosylation of 2-pyrimidinone. These findings are also compatible with the metal-doped-clay model developed by our lab for the unified route of the selection of ribose and subsequent syntheses of nucleotide and RNA.

Background: Observational health data has the potential to be a rich resource to inform clinical practice and regulatory decision making. However, the lack of standard data quality processes makes it difficult to know if these data are research ready. The EHDEN COVID-19 Rapid Col-laboration Call presented the opportunity to assess how the newly developed open-source tool Data Quality Dashboard (DQD) informs the quality of data in a federated network. Methods: 15 Data Partners (DPs) from 10 different countries worked with the EHDEN taskforce to map their data to the OMOP CDM. Throughout the process at least two DQD results were collected and compared for each DP. Results: All DPs showed an improvement in their data quality between the first and last run of the DQD. The DQD excelled at helping DPs identify and fix conformance is-sues but showed less of an impact on completeness and plausibility checks. Conclusions: This is the first study to apply the DQD on multiple, disparate databases across a network. While study-specific checks should still be run, we recommend that all data holders converting their data to the OMOP CDM use the DQD as it ensures conformance to the model specifications and that a database meets a baseline level of completeness and plausibility for use in research.

The aim is to evaluate a program for direct oral anticoagulants (DOACs) management in nonvalvular atrial fibrillation (NVAF) patients, according to patient profiles, appropriateness of dosing, patterns of crossover, effectiveness and safety. This is an observational and longitudinal retrospective study in a cohort of patients attended in daily clinical practice in a single regional hospital in Spain with a systematic follow-up plan for up to 3 years for patients initiating dabigatran, rivaroxaban or apixaban between JAN/2012-DEC/2016. We analyzed 490 episodes of treatment (apixaban 2.5 mg: 9.4%, apixaban 5 mg: 21.4%, dabigatran 75 mg: 0.6%, dabigatran 110 mg: 12,4%, dabigatran 150 mg: 19.8%, rivaroxaban 15 mg: 17.8% and rivaroxaban 20 mg: 18.6%) in 445 patients. 13.6% of patients on dabigatran, 9.7% on rivaroxaban, and 3.9% on apixaban, switched to other DOACs or changed dosing. Apixaban was the most frequent DOAC switched to. The most frequent reasons for switching were toxicity (23.8%), bleeding (21.4%) and renal deterioration (16.7%). Inappropriateness of dose was found in 23.8% of episodes. Patients taking apixaban 2.5 mg were older, had higher CHA2DS2VASc score and lower creatinine clearance. Patients taking dabigatran 150 mg and rivaroxaban 20 mg were younger, had lower CHA2DS2VASc and higher creatinine clearance. Rates of stroke/transient ischemic attack (TIA) were 1.64/0.54 events/100 patients-years, while rates of major, clinically relevant non-major (CRNM) bleeding and intracranial bleeding where 2.4, 5, and 0.5 events/100 patients-years. Gastrointestinal and genitourinary bleeding were the most common type of bleeding events (BE). On multivariable analysis, prior stroke (RR: 4.2; CI: 1.5-11.8; p=0.006) and age (RR: 1.2; CI: 1.1-1.4; p=0.006) were independent predictors of stroke/TIA. Concurrent platelet inhibitors (RR: 7.1; CI: 2.3-21.8; p=0.001), male gender (RR: 2.1; CI: 1.2-3.7; p=0.0012) and age (RR: 1.1; CI: 1.02-1.13; p=0.005) were independent predictors of BE. This study complements the scant data available on the use of DOACs in NVAF patients in Spain, confirming a good safety and effectiveness profile

The evolutionary origin of the genome remains elusive. Here, I hypothesize that its first iteration, the protogenome, was a multi-ribozyme RNA. It evolved, likely within liposomes (the protocells) forming in dry-wet cycling environments, through the random fusion of ribozymes by a ligase and was amplified by a polymerase. The protogenome thereby linked, in one molecule, the information required to seed the protometabolism (a combination of RNA-based autocatalytic sets) in newly forming protocells. If this combination of autocatalytic sets was evolutionarily advantageous, the protogenome would have amplified in a population of multiplying protocells. It likely was a quasispecies with redundant information, e.g., multiple copies of one ribozyme. As such, new functionalities could evolve, including a genetic code. Once one or more components of the protometabolism were templated by the protogenome (e.g., when a ribozyme was replaced by a protein enzyme), and/or addiction modules evolved, the protometabolism became dependent on the protogenome. Along with increasing fidelity of the RNA polymerase, the protogenome could grow, e.g., by incorporating additional ribozyme domains. Finally, the protogenome could have evolved into a DNA genome with increased stability and storage capacity. I will provide suggestions for experiments to test some aspects of this hypothesis.

Three cohorts including the Fire Department of the City of New York (FDNY), the World Trade Center Health Registry (WTCHR), and the General Responder Cohort (GRC), each funded by the World Trade Center Health Program have reported associations between WTC-exposures and cancer. Results have generally been consistent with effect estimates for excess incidence for all cancers ranging from 6 to 14% above background rates. Pooling would increase sample size and de-duplicate cases between the cohorts. Pooling required time consuming steps: obtaining IRB approvals and legal agreements from entities involved; establishing an honest broker for managing the data; de-duplicating the pooled cohort files; applying to State Cancer Registries (SCRs) for matched cancer cases; and finalizing analysis data files. Obtaining SCR data use agreements ranged from 6.5 to 114.5 weeks with six states requiring >20 weeks. Records from FDNY (n=16,221), WTCHR (n=29,372), and GRC (n=33,427) were combined de-duplicated resulting in 69,102 unique individuals. Overall, 7,894 cancer tumors were matched to the pooled cohort, increasing the number cancers by as much as 58% compared to previous analyses. Pooling resulted in a coherent resource for future research for studies on rare cancers and mortality, with more representative of occupations and WTC- exposure.

The existence of a common ancestor to all living organisms in Earth is a necessary corollary of Darwin idea of common ancestry. The Last Universal Common Ancestor (LUCA) has been normally considered as the ancestor of cellular organisms that originated the three domains of life: Bacteria, Archaea and Eukarya. Recent studies about the nature of LUCA indicate that this first organism should present hundreds of genes and a complex metabolism. Trying to bring another of Darwin ideas into the origins of life discussion, we went back into the prebiotic chemistry trying to understand how LUCA could be originated under gradualist assumptions. Along this line of reasoning, it became clear to us that the definition of another ancestral should be of particular relevance to the understanding about the emergence of biological systems. Together with the view of biology as a language for chemical translation, on which proteins are encoded into nucleic acids polymers, we glimpse a point in the deep past on which this Translation mechanism could have taken place. Thus, we propose the emergence of this process shared by all biological systems as a point of interest and propose the existence of this pre-cellular entity named FUCA, as the First Universal Common Ancestor. FUCA was born in the very instant on which RNA-world replicators started to be capable to catalyze the bonding of amino acids into oligopeptides. FUCA has been considered mature when the translation system apparatus has been assembled together with the establishment of a primeval, possibly error-prone genetic code. This is FUCA, the earliest ancestor of LUCA’s lineage.

Hosting FIFA World Cup obviously produce immense socio-economic impacts to a nation. Proximal non-host city perception to mega event was frequently explored, while distal non-host city perception has less investigated. This study assessed the socio-economic impacts of FIFA World Cup Qatar 2022 in Chon Buri Sports City residents. Participants were 422 Chon Buri Sports City residents from eleven districts. Perception on socio-economic impacts of hosting FWC Qatar 2022 was measured from the translated Scale of Perceived Social Impacts. Extracted seven dimensions by confirmatory factor analysis is consistent with empirical data. Positive impact dimensions are Community Development, Community Pride, Economic Benefits. Negative impact dimensions are Traffic Problems, Security Risks, Economic Costs, and Environmental Concerns. Chon Buri Sports City residents perceived fewer negative impacts than other non-host city residents. Positive impacts of hosting FWC Qatar 2022 has more influenced on Chon Buri Sports City residents’ perception than negative impacts. These findings advantage for sport stakeholders to deeper understand the impacts of mega event hosting.

This paper aims to establish lighting as a key facilitator in the placemaking processes for World Heritage Sites. Placemaking is a process of designing, managing, planning and programming the development of shared public spaces within the urban fabric. Research methods inspired from ethnography such as interviews, observations and questionnaires are used to gather data from three main groups of people related to the lighting of World Heritage Sites namely: heritage experts, lighting designers, and locals and visitors. Two UNESCO designated World Heritage Sites are investigated as case studies: Saint-Avit-Sénieur in Dordogne, France and Naghshe-Jahan-Square in Isfahan, Iran. Thematic analysis of the data collected from these investigations reveal key lighting characteristics and lighting design considerations that can facilitate the placemaking process for World Heritage Sites. The lighting characteristics include: avoiding over-lighting, overly theatrical lighting and uniform lighting; balancing floodlighting; preventing glare; providing flexible and harmonious lighting. The lighting design considerations include: accounting meanings and values; amplifying narratives; balancing genders; building attraction and excitement; creating layers; enhancing atmospheres; ensuring safety; improving functionality; offering interpretations; and supporting activities.

The two major global immunisation agenda framings (Missed Opportunity for Immunisation, MOI vs Immunisation Defaulting) are interchangeably and inappropriately used in public health research and practice with flawed or misleading strategies recommended and adopted in various settings globally. This is evident in the fact that many opportunities to adopt evidence/findings from immunisation coverage research in policy are grossly missed. Ineffectiveness of inappropriate interventions from biased evidence can discourage and mislead the governance to make radical decisions by discretion. This could be the reason for the inability of low-and middle-income countries to vaccinate 80% of their children and otherwise; this also poses a global health threat to capable nations. The current guideline and information on MOI and immunisation defaulting appear insufficient and a little clarification on it would assist forerunners in immunisation to achieve measurable progress in ensuring good coverage especially in low-and middle-income countries. Consequently, this paper is aimed at addressing this issue in immunisation practice with appropriate recommendations. Optimistically, this will stimulate further discussions, streamline differences, and gear global immunisation governance on the subject matter, to achieve the target coverage by 2030 in low-and middle-income countries.

The "best of all possible worlds" theory (hereinafter the "possible world theory") was presented by Leibniz many centuries ago, and provided an opportunity for metaphysics to understand the ontological meaning of the world in an in-depth way. Furthermore, the theory has multiple impacts on the multiverse theory of modern physics. However, considering the ontological questions of the world solely on linguistics logic leads to basing the possible world theory or the multiverse theory on relatively uncertain inferential reasons. In this study, symbolic logic was used to consider the possible world theory on a more solid foundation. The entire world was made into oneness, and tracking the existential process at the beginning of the world, realized the existential necessity of the world, even though the initial causal point of the world was assumed to be completely void (null set). The existential system in this study, was generalized without specific elements, apart from existence and non-existence. It was discovered that existential possibility and existential necessity are logically equivalent.

In cognitive radio systems, identifying spectrum opportunities is fundamental to efficiently use the spectrum. Spectrum occupancy prediction is a convenient way of revealing opportunities based on previous occupancies. Studies have demonstrated that usage of the spectrum has a high correlation over multidimensions which includes time, frequency, and space. Accordingly, recent literature uses tensor-based methods to exploit the multidimensional spectrum correlation. However, these methods share two main drawbacks. First, they are computationally complex. Second, they need to re-train the overall model when no information is received from any base station for any reason. Different than the existing works, this paper proposes a method for dividing the multidimensional correlation exploitation problem into a set of smaller sub-problems. This division is achieved through composite two-dimensional (2D)-long short-term memory (LSTM) models. Extensive experimental results reveal a high detection performance with more robustness and less complexity attained by the proposed method. The real-world measurements provided by one of the leading mobile network operators in Turkey validate these results.

Adaptive bitrate (ABR) algorithms optimize the quality of streaming experiences for users in client-side video players especially in unreliable or slow mobile networks. Several rule-based heuristic algorithms can achieve stable performance, but they sometimes fail to adapt properly to changing network conditions. Fluctuating bandwidth may cause algorithms to default to behavior that creates a negative experience for the user. ABR algorithms can be generated with reinforcement learning, a decision-making paradigm in which an agent learns to make optimal choices through interactions with an environment. Training reinforcement learning algorithms for bitrate streaming requires building a simulator for an agent to experience interactions quickly; training an agent in the real environment is infeasible due to the long step times in real environments. This project explores using supervised learning to construct a world-model, or a learned simulator, from recorded interactions. A reinforcement learning agent trained inside of the learned model, rather than a simulator, can outperform rule-based heuristics. Furthermore, agents trained inside the learned world-model can outperform model-free agents in low sample regimes. This work highlights the potential for world-models to quickly learn simulators, and to be used to generate optimal policies.

We show that the Einstein field equations for a five-dimensional warped spacetime, where only gravity can propagate into the bulk, determine the dynamical evolution of the warp factor of the four-dimensional brane spacetime. This can be explained as a holographic manifestation. The warped 5D model can be reformulated by considering the warp factor as a dilaton field ($\omega$) conformally coupled to gravity and embedded in a smooth $M_4 \otimes R$ manifold. On the brane, where the U(1) scalar-gauge fields live, the dilaton field manifests itself classically as a warp factor and enters the evolution equations for the metric components and matter fields. We write the Lagrangian for the Einstein-scalar-gauge fields in a conformal invariant setting. However, as expected, the conformal invariance is broken (trace-anomaly) by the appearance of a mass term and a quadratic term in the energy-momentum tensor of the scalar-gauge field, arising from the extrinsic curvature terms of the projected Einstein tensor. These terms can be interpreted as a constraint in order to maintain conformal invariance. By considering the dilaton field and Higgs field on equal footing on small scales, there will be no singular behavior, when $\omega\rightarrow 0$ and one can deduce constraints to maintain regularity of the action. Our conjecture is that $\omega$, alias warp factor, has a dual meaning. At very early times, when $\omega \rightarrow 0$, it describes the small-distance limit, while at later times it is a warp (or scale) factor that determines the dynamical evolution of the universe. We also present a numerical solution of the model and calculate the (time-dependent) trace-anomaly. The solution depends on the mass ratio of the scalar and gauge fields, the parameters of the model and the vortex charge $n$.

Objective: To perform a systematic review of real-world outcomes for anti-CGRP-mAbs. Methods: Following the PRISMA guidelines, we searched PubMed for real-world data of Erenumab, Galcanezumab, Fremanezumab, or Eptinezumab in patients with migraine. Results: We identified 104 publications (73 retrospective), comprising 8 pharmaco-epidemiologic and 63 clinic-based studies, 30 case reports and 3 other articles. None of the clinic-based studies provided follow-up data over more than one year in more than 200 patients. Findings suggest reductions in health insurance claims and days with sick-leave as well as better treatment adherence with anti-CGRP-mAbss. Effectiveness, reported in 59 clinic-based studies, was comparable to randomized controlled trials. A treatment pause was associated with an increase in migraine frequency and switching to another antibody resulted in a better response in some of the patients. Adverse events and safety issues were addressed in 70 papers including 22 single case reports. Conclusion: Real-world data on anti-CGRP-mAbs are limited by retrospective data collection, small patient numbers and short follow-up periods. The majority of papers seem to support good effectiveness and tolerability of anti-CGRP-mAbs in the real-world setting. There is an unmet need for large prospective real-world studies providing long-term follow-up of patients treated with anti-CGRP-mAbs.

To both survive and develop continuously, enterprises must overcome many kinds of competition and challenges. Cultivating employees' active and sustainable organizational citizenship behavior is important for enterprises to successfully cope with turbulence and uncertain events during their development. In this study, we investigated the development level of and factors influencing employees' organizational citizenship behavior in current organizations. By using the Belief in a Just World Scale, Organizational Citizenship Behavior Scale, and Interpersonal Intelligence Scale, we investigated 230 employees from 15 different enterprises. The results showed that belief in a just world, interpersonal intelligence, and organizational citizenship behavior were significantly positively correlated. Interpersonal intelligence played a moderating role between belief in a just world and organizational citizenship behavior; the organizational citizenship behavior of individuals with high interpersonal intelligence increased with the strengthening of the belief in a just world, and this increase was larger than that experienced by individuals with low interpersonal intelligence. This meant that under a certain level of belief in a just world, a high level of interpersonal intelligence was more conducive to promoting employees' sustainable organizational citizenship behavior.

Private vehicle travel is the most basic mode of transportation, and the effective control of the real-world fuel consumption rate of light-duty vehicles plays a vital role in promoting sustainable economic development as well as achieving a green low-carbon society. Therefore, the impact factors of individual carbon emission must be elucidated. This study builds five different models to estimate real-world fuel consumption rate of light-duty vehicles in China. The results reveal that the Light Gradient Boosting Machine (LightGBM) model performs better than the linear regression, Naïve Bayes regression, Neural Network regression, and Decision Tree regression models, with mean absolute error of 0.911 L/100 km, mean absolute percentage error of 10.4%, mean square error of 1.536, and R squared (R2) of 0.642. This study also assesses a large number of factors, from which three most important factors are extracted, namely, reference fuel consumption rate value, engine power and light-duty vehicle brand. Furthermore, a comparative analysis reveals that the vehicle factors with greater impact on real-world fuel consumption rate are vehicle brand, engine power, and engine displacement. Average air pressure, average temperature, and sunshine time are the three most important climate factors.

This study reports the likely real-world effects of fleet replacement with electric vehicles (EVs) and higher efficiency EURO6 vehicles on the exhaust emissions of NOx, PM, and CO2 in the seven boroughs of the West Midlands (WM) region, UK. National fleet composition data, local EURO distributions and traffic compositions were used to project vehicle fleet compositions for different roads in each borough. A large dataset of real-world emission factors including over 90,000 remote-sensing measurements, obtained from remote sensing campaigns in five UK cities, was used to parameterise the emission profiles of the studied scenarios. Results show that adoption of the fleet electrification approach would have the highest emission reduction potential on urban roads in WM boroughs. It would result in maximum reductions ranging from 35.0-37.9%, 44.3-48.3%, 46.9-50.3% for NOx, PM, and CO2, respectively. In comparison, the EURO6 replacement fleet scenario would lead to reductions ranging from 10.0-10.4%, 4.0-4.2%, and 6.0-6.4% for NOx, PM, and CO2, respectively. The studied mitigation scenarios have higher efficacies on motorways than on rural and urban roads because of the differences in traffic fleet composition. The findings presented will help policymakers choose climate and air quality mitigation strategies.

Building Country Resilience is a long-term process particularly in the hyper connected world we are living today; and depends on good governance and appropriate equilibrium of respect for people, planet and profits as well as avoiding depleting natural resources that end up affecting the biosphere. Hence represent a most needed Learning ability that may be seeing to be related to the process of Sustainable Development. So, this paper seeks to find best practices and a Ranking of Countries that may help as guides to foster Country Resilience. For this purpose, it was developed a World Resilience Index - WRI based on a Statistical Analysis with updated data from 108 Countries divided into 3 Groups: American Countries – AMER (20 Countries), Advanced Economies - AVECO (22 Countries) mostly from Europe and OTHER (66 Countries); and using a set of Synthetic Variables like the Social Progress Index – SPI, the Environmental Performance Index – EPI, and the Sustainable Development Goals Index – SDGI, besides some related to Governance and the World Risk Index – WRI.

Systems Chemistry has been a key component of origin of life research, invoking models of life’s inception based on evolving molecular networks. One such model is the Graded Autocatalysis Replication Domain (GARD) formalism embodied in a Lipid World scenario, which offers rigorous computer simulation based on defined chemical kinetics equations. GARD suggests that the first pre-RNA life-like entities could have been homeostatically-growing assemblies of amphiphiles, undergoing compositional replication and mutations, as well as rudimentary selection and evolution. Recent progress in Molecular Dynamics has provided an experimental tool to study complex biological phenomena such as protein folding, ligand-receptor interactions and micellar formation, growth and fission. The detailed molecular definition of GARD and its inter-molecular catalytic interactions make it highly compatible with Molecular Dynamics analyses. We present a roadmap for simulating GARD’s kinetic and thermodynamic behavior using various Molecular Dynamics methodologies. We review different approaches for testing the validity of the GARD model, by following micellar accretion and fission events and examining compositional changes over time. Near future computational advances could provide empirical delineation for further system complexification, from simple compositional non-covalent assemblies towards more life-like protocellular entities with covalent chemistry that underlies metabolism and genetic encoding.

Purpose: To meet the challenges of the precision medicine era, quality assessment of shared sarcoma care becomes pivotal. The MDT approach is the most important parameter for succesfull outcome. Because of all MDTs disciplines surgery is the key step to render sarcoma patients disease free, defining the spectrum of a sarcoma surgeon is critical. To the best of the authors knowledge, a comprehensive interoperable digital platform to assess the scope of sarcoma surgery and the experience of a sarcoma surgeon in its full complexity is lacking. Methods: A web-based real-world data (RWD) registry on sarcoma surgery has been created to assess the clinical exposure, tumor characteristics, and surgical settings and techniques applied for both resections and reconstructions of sarcomas and thereby the surgical exposure of an individual surgeon over time. Results: During 10 years, there were 723 sarcoma board/MDT meetings discussing 3130 patients. A total of 1094 patients underwent 1250 surgical interventions on mesenchymal tumors by one single sarcoma surgeon. These included 615 deep soft tissue tumors (197 benign, 102 intermediate, 281 malignant, 27 simulator, 7 metastasis, 1 blood), 116 superficial soft tissue tumors (45 benign, 12 intermediate, 40 malignant, 18 simulator, 1 blood) and 519 bone tumors (129 benign, 112 intermediate, 182 malignant, 18 simulator, 46 metastasis, 14 blood and 18 sequelae of 1st treatment). Detailed types of resections and reconstructions were analyzed. Conclusion: A web-based RWD sarcoma surgeon registry with transparent real-time descriptive analytics is feasible and enables large scale definition of the surgical complexity and ultimately quality of sarcoma care.

Protected areas, such as natural World Heritage sites, RAMSAR wetlands, and Biosphere reserves are ecosystems within landscapes. Each site meets certain criteria that allow it to qualify as heritage or protected. Both climate change and human influence (e.g., incursion, increased tourist visitation) are altering biophysical conditions at many such sites. As a result, conditions at many sites are falling outside the criteria for their original designation. The alternatives are to change the criteria, remove protection from the site, change site boundaries such that the larger or smaller landscape meets the criteria, or manage the existing landscape in some way that reduces the threat. This paper argues for adaptive heritage, an approach that explicitly recognizes changing conditions. We discuss the need to view heritage areas as parts of a larger landscape, and to take an adaptive approach to management of that landscape. We offer five themes of adaptive heritage: 1) treat sites as living heritage, 2) employ innovative governance, 3) embrace transparency and accountability, 4) invest in monitoring and evaluation, and 5) manage adaptively. We offer the Australian Wet Tropics as an example where aspects of adaptive heritage currently are practiced, highlighting the tools being used. This paper offers guidance supporting decisions about natural heritage in the face of climate change and non-climatic pressures. Rather than delisting or lowering standards, we argue for adaptive approaches.

More than 179,000 individuals have fallen ill of the Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus, which first emerged in China less than four months ago in December 2019. As of today, there exist no approved treatments against COVID-19. Vaccines are being developed, but they will take time, at least one year, to reach the population. Drug repositioning represents a fast track because already approved medicines have been broadly tested through multiple trials. We developed a repositioning strategy that mostly leads to candidates that are commonly used. The advantages are that they will facilitate proof of concept in humans through a “real-world evidence” approach and should be rapidly available to the population. We focus on the established research results that the unfolded protein response (UPR) and autophagy pathways of the host cells are essential to the life cycle of previously known coronaviruses. We performed the relevant bioinformatics analysis to understand and confirm if SARS-CoV-2 may interact with these druggable pathways. Based on these considerations, we prioritized two additional druggable pathways, which are important to the viral life cycle and tightly connected to UPR/autophagy signaling: the mitochondrial permeability transition pores (MPTP) and NLRP-3 inflammasome pathways. These four important pathways are perturbed in most major common diseases and have therefore been targeted by numerous broadly prescribed drugs. We have identified 97 approved drugs that are known to modulate these four identified pathways, and which represent, therefore, interesting repositioning candidates. Although it is indisputable that these drugs should never be used for immediate self-medication against COVID-19, we notice that some of them could also be prescribed to individuals who have COVID-19 comorbidities (e.g., hypertension). It is debated if these comorbidities are linked to the pathology itself (e.g., hypertension) or the drugs used to treat the pathology (e.g., sartans). Therefore, relevant preclinical tests and massive electronic health records (i.e., real-world evidence) must be used to pre-screen them and check the COVID-19 prognosis of individuals taking these drugs.

The World economy after global crisis of 2008–2009 entered a restructuring era. It defines relevance of researches of its directions and patterns. The principles of determinism and systemic analysis are methodological basis of article. In research were used the methods of processing Big Date, as of continuous changes and the symmetric analysis of macroeconomic indicators according to databases of the IMF, WB, BIS, the Central banks and treasuries. As a result of the research it is proved that depth and globalism of recessionary processes are caused by a combination of crisis of world financial system and civilization problems. Intrinsic signs of risks in the modern economy caused by the duality of the nature of global crises have been identified. There are analyzes: the deficit of resources of the international financial institutions, a negative role of a fixed rate of Yuan, a big share of derivatives and off-balance obligations of banks, use of SPV in structures of deals, growth of debt obligations, trade wars, slowdown in the growth of the Chinese economy, aggravation of contradictions between global and national finances. The thesis is reasonable that deglobalization and dedollarization deepened this conflict, started the rollback mechanism from achievements of globalization, led to tariff wars. By means of a systematization it is proved the key directions of the restructuring of global economy: legal basis, leadership and reserve currency. On the basis of SWOT-analysis of the USA and China it was concluded that the question of leadership of one country should be excluded, but slow transition to use SDR (with a basket from 15–20 currencies) as a reserve.

Disaster Risk Reduction (DRR) is a high priority on the agenda of main stakeholders involved in sustainable development and Earth Observation (EO) can provide useful, timely and economical information in this context. This short communication outlines the European Space Agency’s (ESA) specific initiative to promote the use and uptake of satellite data in the global development community: ‘Earth Observation for Sustainable Development (EO4SD)’. One activity area under EO4SD is devoted to Disaster Risk Reduction: EO4SD DRR. Within this project, a team of European companies and institutions are tasked to develop EO services for supporting the implementation of DRR in International Financial Institutions’ (IFI) projects. Integration of satellite-borne data and ancillary data to generate insight and actionable information is thereby considered a key factor for improved decision making. To understand and fully account for the essential user requirements (IFI & Client States), engagement with technical leaders is crucial. Fit-for-purpose use of data and comprehensive capacity building eventually ensure scalability and long-term transferability. Future perspectives of EO4SD and DRR regarding mainstreaming are also highlighted.

The article addresses the function of (post)colonial nostalgia in a context of multidirectional memory (Rothberg 2009) in contemporary Europe. How can different cultural memories of the Second Word War be put into respectful dialogue with each other? The text is based on a contrapuntal reading (Said 1994) of British and Egyptian popular narratives, using a qualitative content analysis of 10 British tv documentary films about the North Africa Campaign, and data from qualitative interviews collected during ethnographic fieldwork in Alexandria and Cairo, Egypt, during visits 2013--2015. The study highlights considerable differences between the British and Egyptian narratives, but also significant similarities regarding the use and function of nostalgia. In addition, the Egyptian narrative expresses a profound cosmopolitan nostalgia and a longing for what is regarded as Egypt’s lost, modern Golden Age, identified as the decades before the nation’s fundamental change from western-oriented monarchy to Nasser’s Arab nationalist military state. The common elements between the two national narratives indicate a possibly fruitful way to open up for a shared popular memory culture about the war years, including postcolonial aspects.

The transition from the Peptide/RNA world to the Protein/RNA world in the hydrothermal vent environment was a major event in the history of life. The advent of proteins utterly changed the conditions of emerging life, representing a watershed in its development. During subsequent translation various protein enzymes emerged driving protocells into a more complex and interconnected system. With their astonishing versatility, the protein enzymes catalyzed crucial biochemical reactions within protocells into more complex biomolecules in diverse metabolic pathways, whereas structural proteins provided strength and permeability in the cell membrane. Four major events followed after availability of various kinds of protein molecules during prebiotic synthesis. These are: (1) the modification of the phospholipid membrane into the plasma membrane; (2) the origin of primitive cytoplasm; (3) the beginnings of the virus world; and (4) the advent of DNA. The first innovation mediated by proteins was the improvement of the cell membrane. The phospholipid membrane was initially evolved in a vent environment from the gradual modification of a fatty acid membrane via an intermediate phosphatidate acid by non-enzymatic reactions. The phospholipid is then synthesized from phosphatidate acid by a series of enzymes. To make the phospholipid membrane more permeable, various protein molecules interacted with the cell membrane. Proteins not only stabilized the wall membrane, but also acted as pumps, preventing some molecules from the protocells from crossing the membrane barriers, while permitting other selected molecules and ions to enter and leave the protocell. The second modification led by proteins is the gradual conversion of the interior of the protocell from a water-like medium into a gel-like cytoplasm, which became the storehouse of a wide range of biomolecules including amino acids, proteins, nucleic acids, ribosomes, as well as salt and water. The third innovation utilizing the newly synthesized proteins was the emergence of the ancient virus world. In the milieu of different kinds of mRNAs in the prebiotic soup, jelly-roll capsid genes originated de novo within genomes of nonviral mRNAs by overprinting. These fragile capsid genes were possibly coated by proteins on the mineral substrate for stability and durability, transforming them into ancient viral particles. These protein coats were random and were not encoded by encased genes. Some protocells might have engulfed these viral particles, when the capsid genes utilized the ribosomes of the host to translate into the appropriate capsid proteins. These capsid proteins then coated the viral genes to make new copies of primordial viruses inside the protocell. Since then, viruses became capsid-encoding organisms. These primordial mRNA viruses parasitized RNA-based protocells, manipulating them to make new copies of themselves. This was the beginning of a relentless war between viruses and their protocellular hosts. The next stage in viral evolution was the emergence of a primitive retrovirus (pre-retrovirus) with a new kind of replicative strategy in a sense that it could turn its RNA into DNA using its own reverse transcriptase enzyme. This is the beginning of the Retro world that facilitated the transition from RNA to DNA genomes. The infection of RNA protocells with pre-retroviruses progressively transferred the RNA genome to a viral DNA genome by retro-transcription. The advent of DNA by the pre-retrovirus marks the fourth innovation, when a number of enzymes had already developed and were utilized by pre-retroviruses. With continued infection, DNA viruses slowly transferred not only their core replication enzymes, such as helicase, primase, and DNA polymerase, to RNA protocells, but also to their DNAs as well. Thus, began the DNA world, when DNA replaced RNA as the major genome of the protocells. With the advent of DNA, replication of information was entirely dissociated from its expression. Because DNA is much more stable than mRNA with more storage capacity, it is a superb archive for information systems in the form of base sequences. DNA progressively took over the replicative storage function of mRNA, leaving the latter for protein synthesis. The new protocell with the DNA genome will diversify into large populations of DNA protocells that will outcompete populations of RNA protocells. Genetic information began to flow from DNA to mRNA to protein in a two-step process involving transcription and translation. In the biological stage, DNA replication was central to the binary fission of the first cell, orchestrated by the duplication of genomes and then the division of the parent cell into two identical daughter cells. It was carried out by a set of enzymes that formed a Z-ring at the site of replication. With the onset of binary fission, the population of primitive cells grew rapidly in the hydrothermal vent environment, undergoing Darwinian evolution and diversification. These primordial hyperthermophiles, presumably the first life, obtained food and energy directly from the vent environment. However, such a situation was self-limiting, so the early cells evolved their own mechanisms for generating metabolic energy and synthesizing the molecules necessary for their reproduction. The earliest fossil record (≥ 3.5 Ga) of biotic activity is preserved in the Archean hydrothermal and sedimentary rocks of the Nuvvuagittuq Craton of Canada, the Isua Craton of Greenland, the Pilbara Craton of Australia, the Kaapvaal Craton of South Africa, and the Singhbhum Craton of India in the form of the carbonaceous remains of microbial cells, cellular microfossils, and stromatolites. These microscopic fossils provide crucial evidence of the origin and early evolution of prokaryotic cells, beginning with hyperthermophiles. Molecular phylogenetic analysis suggests that both domains of life ¬– Bacteria and Archaea probably split from the last universal common ancestor (LUCA), a hyperthermophilic organism. In the younger sequences of these Archean cratons, two kinds of photosynthetic bacteria, anoxygenic green sulfur bacteria, and oxygenic cyanobacteria, appeared in quick succession from the thermophilic ancestor, indicating a shift of niche from a benthic to a planktonic, with reduced thermotolerance. The development of anoxygenic and oxygenic photosynthesis would have allowed life to escape the hydrothermal setting and invade a newly evolved habitat—broad continental shelves to tap solar energy. Cyanobacteria invaded the global ocean, turned it into blue and green, produced oxygen for the first time, and left their signatures in the carbonates and stromatolites.

A new treatment option for cluster headache (CH) prevention is needed. Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) ligands are used as a preventative treatment for migraine. Considering the CGRP’s role in the CH attack’s ignition and upkeep, fremanezumab and galcanezumab have been evaluated for CH preventative treatment. However, only high-dose (300 mg) galcanezumab was proven for episodic CH prevention. We herein report 3 cases of migraine and comorbid CH with previous failures of preventive treatments. The 2 cases were treated with fremanezumab and the one with non-high-dose galcanezumab. All 3 cases showed good results not only on migraine but also on CH attacks. Our report suggested the efficacy of CGRP-mABs for CH prevention. Our cases differed from the cases in the phase 3 trials of CGRP-mABs for CH prevention in the following 2 points. First, the patients had both migraine and comorbid CH. Second, the combined use of CGRP-mABs with preventative drugs for CH, such as verapamil and/or prednisolone, was performed. Future accumulation of real-world data may prove the efficacy of CGRP-mABs for CH prevention.

The emergence of proteins in the prebiotic world was a watershed event at the origin of life. With their astonishing versatility, the protein enzymes catalyzed crucial biochemical reactions within protocells into more complex biomolecules in diverse metabolic pathways, whereas structural proteins provided strength and permeability in the cell membrane. Five major biochemical innovations followed in succession after availability of various kinds of protein molecules during decoding and translation of mRNAs. These are: (1) the modification of the phospholipid membrane into the plasma membrane; (2) the origin of primitive cytoplasm; (3) primitive gene regulation; (4) the beginnings of the virus world; and (5) the advent of DNA. The creative role of viruses during prebiotic synthesis led to the origin of the DNA world, when DNA replaced mRNA as the major genome of the protocells. With the advent of DNA, replication of information was entirely dissociated from its expression. Because DNA is much more stable than mRNA with more storage capacity, it is a superb archive for information systems in the form of base sequences. DNA progressively took over the replicative storage function of mRNA, leaving the latter for protein synthesis. Genetic information began to flow from DNA to mRNA to protein in a two-step process involving transcription and translation. In the biological stage, DNA replication was central to the binary fission of the first cell, orchestrated by the duplication of genomes and then the division of the parent cell into two identical daughter cells. With the onset of binary fission, the population of primitive cells grew rapidly in the hydrothermal vent environment, undergoing Darwinian evolution and diversification by mutation. The habitat of the earliest fossil record (≥ 3.5 Ga) from the Archean sedimentary rocks of Canada, Greenland, Australia, South Africa, and India offers a new window on the early radiation of microbial life. The development of anoxygenic and then oxygenic photosynthesis from early hyperthermophiles would have allowed life to escape the hydrothermal setting to the mesophilic global ocean.

Cities’ delineation remains a hot topic of debate in a time where comparisons between cities are becoming increasingly based on different issues that address various scales of interventions and thus different concepts of cities. Aiming to compare cities and their insertion into globalization, we suggest that the “urban field of influence” is the best way to approach cities for this specific perspective. However, after reviewing the different existing possible concepts, we replace this concept with four different approaches proposed by Pumain et al. (1992): political entities, morphological agglomerations, functional urban areas and conurbations/Mega city regions. We discuss the top-down and bottom-up existing initiatives launched at the world scale and then use a mixed top-down and bottom-up approach to propose a new delineation of a large urban region (LUR), denoting a concept close to the conurbation or Mega city-region concept. The compositions of these LURs are published as an initial incomplete framework, suggesting the need for further critical comments and contributions to improve them.

In the last decades there has been a progressive aging of the population, known as “demographic revolution” or “demographic transition”. As a consequence of the worldwide progressive aging of population and of the increasing of general life expectancy, the relationship between aging and disability became a very important one and received a huge interest in research for its consequences on participation, inclusion and quality of life of ageing people and for its consequences on socio-sanitary organizations. The aim of this paper is to analyze this relationship and to discuss consequences on participation, inclusion and quality of life of ageing people, according to recent conceptual models of disability and active ageing. According to previous papers this relationship could be considered in two ways: ageing with disability (which refers to people living with long-term effects of disabling conditions acquired from birth to middle age) and disability with ageing (which refers to people which disabling conditions acquired later or age-related conditions), but newer papers proposed a convergence of these two approaches, taking into account the similarities and the differences between the two ways.

Two Iron Age settlements, Tuzusai and Taldy Bulak 2 (ca. 500 BCE to 1 CE), located in Southeastern Kazakhstan on the Talgar alluvial fan north of the Tian Shan range, have yielded a small collection of bone, antler/horn, bronze, and stone artifacts with affinity to nomadic art of the first millennium BCE. Both settlements date within the period of late Saka culture. Two pieces have decorative ornamentations with zoomorphic imagery: a small carved fragment of a with carved images of a wing and an ear and a perforated bone disk with the carving of three birds’ heads. The other artifacts include objects associated with Saka weaponry or nomadic economy such as the two antler/horn psalia (cheek pieces) and a bronze amulet. A carnelian bead will also be described as an imported object. These special finds are found on the occupation floors of mud brick houses and pit houses of settlements, not in grave or burial contexts. The objects are placed in stratigraphic sequence in the settlement sites. Then the method for placing these objects within the chronological framework of “animal-style art” is through comparisons with similar objects found throughout Eurasia—a method used in Soviet and Post-Soviet archaeology. The results show that functional and stylistic elements of the six objects indicate that the Talgar settlements were part of a larger world-system of trade and communication along the early Silk Route(s).

Falls, highly common in the constantly increasing global aging population, can have a variety of negative effects on their health, well-being, and quality of life, including restricting their capabilities to conduct Activities of Daily Living (ADLs), which are crucial for one’s sustenance. Timely assistance during falls is highly necessary, which involves tracking the indoor location of the elderly during their diverse navigational patterns associated with ADLs to detect the precise location of a fall. With the decreasing caregiver population on a global scale, it is important that the future of intelligent living environments can detect falls during ADL.s while being able to track the indoor location of the elderly in the real world. Prior works in these fields have several limitations, such as – the lack of functionalities to detect both falls and indoor locations, high cost of implementation, complicated design, the requirement of multiple hardware components for deployment, and the necessity to develop new hardware for implementation, which make the wide-scale deployment of such technologies challenging. To address these challenges, this work proposes a cost-effective and simplistic design paradigm for an Ambient Assisted Living system that can capture multimodal components of user behaviors during ADLs that are necessary for performing fall detection and indoor localization in a simultaneous manner in the real world. Proof of concept results from real-world experiments are presented to uphold the effective working of the system. The findings from two comparison studies with prior works in this field are also presented to uphold the novelty of this work. The first comparison study shows how the proposed system outperforms prior works in the areas of indoor localization and fall detection in terms of the effectiveness of its software design and hardware design. The second comparison study shows that the cost for the development of this system is the least as compared to prior works in these fields, which involved real-world development of the underlining systems, thereby upholding its cost-effective nature.

Tuberculosis cause of death worldwide and the leading cause from a single infectious agent, ranking above Human immunodeficiency virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). The aim of this study is to ascertain the trend of tuberculosis prevalence and the effect of HIV prevalence onl Tuberculosis case in some West African countries from 2000 to 2016 using count panel data regression models. The data used annual HIV and Tuberculosis cases spanning from 2000 to 2016 extracted from online publication of World health Organization (WHO). Panel Poisson regression model and Negative binomial regression model for fixed and random effects were used to analyzed the count data, the result revealed a positive trend in TB cases while increased in HIV cases leads to increase in TB cases in West African countries. Among the competing models used in this study, Panel Negative Binomial Regression Model with fixed effect emerged the best model with log likelihood value of -1336.554. This study recommended that Government and NGOs need more strategies to fight against HIV menace in West Africa as this will in turn reduced TB cases in West Africa.

The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines which are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.

Recent improvements in deepfake creation have made deepfake videos more realistic. Moreover, open-source software has made deepfake creation more accessible, which reduces the barrier to entry for deepfake creation. This could pose a threat to the people’s privacy. There is a potential danger if the deepfake creation techniques are used by people with an ulterior motive to produce deepfake videos of world leaders to disrupt the order of countries and the world. Therefore, research into the automatic detection of deepfaked media is essential for public security. In this work, we propose a deepfake detection method using upper body language analysis. Specifically, a many-to-one LSTM network was designed and trained as a classification model for deepfake detection. Different models were trained by varying the hyperparameters to build a final model with benchmark accuracy. We achieved 94.39% accuracy on the deepfake test set. The experimental results showed that upper body language can effectively detect deepfakes.

The current SARS- CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS- CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.

Information is the currency of life, but the origin of prebiotic information remains a mystery. We propose transitional pathways from the cosmic building blocks of life to the complex prebiotic organic chemistry that led to the origin of information systems. The prebiotic information system, specifically the genetic code, is segregated, linear, and digital and probably appeared during biogenesis four billion years ago. In the peptide/RNA world, lipid membranes randomly encapsulated amino acids, RNA, and protein molecules, drawn from the prebiotic soup, to initiate a molecular symbiosis inside the protocells. This endosymbiosis led to the hierarchical emergence of several requisite components of the translation machine: tRNAs, aaRS, mRNAs, and ribosomes. When assembled in the right order, the translation machine created biosynthetic polypeptides, a process that transferred information from mRNAs to proteins. This was the beginning of the prebiotic information age. The molecular attraction between tRNA and amino acids led to different stages of the translation machines and the genetic code. tRNA is an ancient molecule that designed and built mRNA for storing the information of its cognate amino acid. Each mRNA strand became the storage device for the genetic information that encoded the amino acid sequences in triplet nucleotides. As information appeared in the digital languages of the codon within mRNA, and the genetic code for protein synthesis evolved, the prebiotic chemistry then became more organized and directional. The origin of the genetic code is enigmatic; herein we propose an evolutionary explanation: the demand for a wide range of specific enzymes in the peptide/RNA world was the main selective pressure for the origin of information-directed protein synthesis. We review three main concepts on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and the adaptive theory. These three theories are compatible with our coevolution model of the translation machines and the genetic code. We suggest biosynthetic pathways as the origin of the specific translation machines which provided the framework for the origin of the genetic code. During translation, the genetic code developed in three stages coincident with the refinement of the translation machines: GNC code developed by the pre-tRNA/pre-aaRS /pre-mRNA machine, SNS code by the tRNA/aaRS/mRNA machine, and finally the universal genetic code by the tRNA/aaRS/mRNA/ribosome machine. Our hypothesis provides the logical and incremental steps for the origin of the programmed protein synthesis. In order to understand the prebiotic information system better, we converted letter codons into numerical codons in the Universal Genetic Code Table. We have developed a software called CATI (Codon-Amino Acid-Translator-Imitator) to translate randomly chosen numerical codons into corresponding amino acids and vice versa. This conversion has granted us insight into how the translation might have worked in the peptide/RNA world. There is great potential in the application of numerical codons to bioinformatics such as barcoding, DNA mining, or DNA fingerprinting. We constructed the likely biochemical pathways for the origin of translation and the genetic code using the Model-View-Controller (MVC) software framework, and the translation machinery step-by-step. Using AnyLogic software we were able to simulate and visualize the entire evolution of the translation machines and the genetic code. The results indicate that the emergence of the information age from the peptide/RNA world was a watershed event in the origin of life about four billion years ago.

The Late Heavy Bombardment Period (4.1 to 3.8 billion years ago) of heightened impact cratering activity on young Earth is likely the driving force for the origin of life. During the Eoarchean, asteroids such as carbonaceous chondrites delivered the building blocks of life and water to early Earth. Asteroid collisions created innumerable hydrothermal crater lakes in the Eoarchean crust which inadvertently became the perfect cradle for prebiotic chemistry. These hydrothermal crater lakes were filled with cosmic water and the building blocks of life. forming a thick prebiotic soup. The unique combination of exogenous delivery of extraterrestrial building blocks of life, and the endogenous biosynthesis in hydrothermal impact crater lakes very likely gave rise to life. A new symbiotic model for the origin of life within the hydrothermal crater lakes is here proposed. In this scenario, life arose around four billion years ago through five hierarchical stages of increasing molecular complexity: cosmic, geologic, chemical, information, and biological. During the prebiotic synthesis, membranes first appeared in the hydrothermal crater lakes, followed by the simultaneous origin of RNA and protein molecules, creating the RNA/protein world. These proteins were noncoded protein enzymes that facilitated chemical reactions. RNA molecules formed in the hydrothermal crater basin by polymerization of the nucleotides on the montmorillonite mineral substrate. Similarly, the initial synthesis of abiotic protein enzymes was mediated by the condensation of amino acids on pyrite surfaces. The regular wet-dry cycles within the crater lakes assisted further concentration, condensation, and polymerization of the RNAs and proteins. Lipid membranes randomly encapsulated amino acids, RNA, and protein molecules from the prebiotic soup to initiate a molecular symbiosis inside the protocells, this led to the hierarchical emergence of several cell components. As the role of protein enzymes became essential for catalytic process in the RNA/protein world, Darwinian selection from noncoded to coded protein synthesis led to translation systems and the genetic code, heralding the information stage. In this stage, the biochemical pathways suggest the successive emergence of translation machineries such as tRNAs, aaRS, mRNAs, and of ribosomes for protein synthesis. The molecular attraction between tRNA and amino acid led to the emergence of translation machinery and the genetic code. tRNA is an ancient molecule that created mRNA for the purpose of storing amino acid information like a digital strip. Each mRNA strand became the storage device for genetic information that encoded the amino acid sequences in triplet nucleotides. As information became available in the digital languages of the codon within mRNA, biosynthesis became less random and more organized and directional. The original translation machinery was simpler before the emergence of the ribosome than that of today. We review three main concepts on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and adaptive theory. We believe that these three theories are not mutually exclusive, but are compatible with our coevolution model of translations machines and the genetic code. We suggest biosynthetic pathways as the origin of the translation machine that provided the framework for the origin of the genetic code. During translation, the genetic code developed in three stages coincident with the refinement of the translation machinery: GNC code with four codons and four amino acids during interactions of pre-tRNA/pre-aaRS /pre-mRNA, SNS code consisting of 16 codons and 10 amino acids appeared during the tRNA/aaRS/mRNA interaction, and finally the universal genetic code evolved with the emergence of the tRNA/aaRS/mRNA/ribosome machine. The universal code consists of 64 codons and 20 amino acids, with a redundancy that minimizes errors in translation. To address the question of the origin of the biological information system in the RNA/protein world, we converted letter codons into numerical codons in the Universal Genetic Code Table. We developed a software called CATI (Codon-Amino Acid-Translator-Imitator) to translate randomly chosen numerical codons into corresponding amino acids and vice versa, gaining insight into how translation might have worked in the RNA/protein world. We simulated the likely biochemical pathways for the origin of translation and the genetic code using the Model-View-Controller (MVC) software framework, and the translation machinery step-by-step. We used AnyLogic software to simulate and visualize the evolution of the translation machines and the genetic code. We conclude that the emergence of the information age from the RNA/protein world was a watershed event in the origin of life about four billion years ago.