(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lym-phoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analysed patient records (1984–2016) from 27 clinical sites in Eurpe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS), and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. Median (range) times from start of first-line therapy to first R/R MF and from first to second R/R MF were 11.2 (0.3–166.5) and 13.5 (0.0–174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radio-therapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). Median (95% confidence interval [CI]) OS from the diagnosis of first R/R MF was 11.5 (6.5–not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); es-timated median PFS (95% CI) from the time of first R/R MF was 1.3 (1.0–2.1) years. (4) Conclu-sion: High rates of R/R disease were observed after second- and third-line treatments in this re-al-world cohort, with longer median OS in patients receiving non-chemotherapy versus chemo-therapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

Antimicrobial resistance (AMR) is a growing public health issue worldwide that affects the world economy. The concern associated with this issue increased during the COVID-19 pandemic. The misuse of antibiotics during the COVID-19 pandemic will have catastrophic implications for the control of AMR. In 2019, the coronavirus illness COVID-19 first appeared in China. COVID-19 infection is a surface-to-surface communicable disease. It is considered the most vital global health disaster of the century. It has rapidly spread around the world and is the greatest challenge for humankind. This chapter discusses the origin, symptoms, transmission, treatment, and recommendations of the COVID-19 disease.

The connectivity level of last-generation vehicles is constantly on the rise. The combined use of Vehicle-To-Everything (V2X) connectivity and autonomous driving can provide remarkable benefits through the optimization of the route and speed trajectory. In this framework, this paper focuses on vehicle eco-driving optimization in a connected environment. The virtual test rig of a premium segment passenger car was used for generating the simulation scenarios. The benefits, in terms of energy and time savings, that the introduction of V2X communication, integrated with cloud computing, can have in a real-world scenario were assessed. The Reference Scenario is a pre-defined Real Driving Emissions (RDE) compliant route, while the simulation scenarios were generated by assuming two different penetration levels of V2X technologies. The associated energy minimization problem is formulated and solved by means of a global optimization algorithm, i.e., Dynamic Programming (DP). The optimization framework includes information coming from the surrounding environment, e.g., traffic lights state, speed limits, distance to travel, etc. The simulations show that introducing a smart infrastructure along with optimizing the vehicle speed in a real-world route can potentially reduce the required energy by 54% while shortening the travel time by 38%. Finally, a sensitivity analysis is performed on the bi-objective optimization cost function to find a set of Pareto optimal solutions, between energy and travel time minimization.

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.

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.

Invasive fungal infections, notably candidemia, have been associated with COVID-19. The epidemiology of candidemia has significantly changed during the COVID-19 pandemic. We aim to identify the microbiological profile, resistance rates, and outcomes of COVID-19 associated candidemia (CAC) compared to patients with candidemia not associated with COVID-19. We retrospectively collected data on patients with candidemia admitted to the American University of Beirut Medical Center between 2004 and 2022. We compared the epidemiology of candidemia during and prior to the COVID-19 pandemic. Additionally, we compared the outcomes of critically ill patients with CAC to those with candidemia without COVID-19 from March 2020 till March 2022. Among 245 candidemia episodes, 156 occurred prior to the pandemic and 89 during the pandemic. Of the latter, 39 (43.8%) were CAC, most of which (82%) were reported from intensive care units (ICU). Non-albicans Candida (NAC) spp. were predominant throughout the study period (67.7%). Candida auris infection was the most common cause of NAC spp. in CAC. C. glabrata had decreased susceptibility rates to fluconazole and caspofungin during the pandemic period (46.1% and 38.4% respectively). Mortality rate in the overall ICU population during the pandemic was 76.6%, much higher than the previously reported mortality of candidemia from previous studies at our center. There was no significant difference in 30-day mortality between CAC and non-CAC (75.0% vs 78.1%; P =0.76). Performing ophthalmic examination (P = 0.002), CVC removal during the 48 hours following the candidemia (P = 0.008) and identifying the Candida spp. (P = 0.028) were significantly associated with a lower case-fatality rate. The epidemiology of candidemia has been significantly affected by the COVID-19 pandemic at our center. Rigorous infection control measures and proper antifungal stewardship are essential to combat highly resistant species like C. auris.

The WORLD3 world model, which served as the basis for The Club of Rome report The Limits to Growth (1972), was criticized, among other things, for not being able to simulate social interactions. In order to remedy this shortcoming, a research group led by Karl Deutsch at the Berlin Science Center developed a far more comprehensive model between 1979 and 1988 entitled GLOBUS, which was supposed to be able to include political developments in the calculation. This article aims to explain the hopes that were attached to the creation of a further world model and the means by which attempts were made to assert its results. To this end, three genealogical lines of the model -I. as part of the world modeling community, II. as part of quantitative international relations research, III. as part of Karl Deutsch's cybernetic-political science research- will be presented. The data basis and the functioning of GLOBUS are then described. Finally, section VI is devoted to the research group's efforts to make the model "effective".

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.

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.

This study evaluates the incidence and characteristics of adverse events (AEs) following the second COVID-19 booster dose, leveraging Taiwan's distinctive approach of extending booster vaccinations to all citizens, unlike the targeted high-risk group strategies in other countries. Utilizing data from Taipei Veterans General Hospital's Vaccine Adverse Event Reporting System (VAERS) from October 27, 2022, to January 19, 2023, the research examines AEs in 441 out of 1711 second booster recipients, considering factors like age, vaccine brands, and booster combinations. The findings reveal incidence rates (IR) of 25.6% (95% CI: 21.1-30.8) after the first booster and 24.9% (95% CI: 20.5-30.0) after the second, mostly non-serious, with those having AEs post-first booster 5 times more likely to report them again (Incidence rat rato, 5.02, P<0.001). Significantly, switching from the mRNA1273 vaccine to another brand reduced AE risk by 18%. The study underscores that AEs are more repetitive than cumulative with additional booster doses, advocating for personalized vaccination strategies based on individual medical histories and previous vaccine reactions. These insights are valuable for healthcare providers in discussing potential AEs with patients, thereby improving vaccine compliance and public trust, and for policymakers in planning future booster vaccination strategies.

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.

Translation of the genetic code into proteins is the main process across all life and ribosomes are ancient cellular machines uniquely enabling this information transformation. We provide a brief overview of the recent advances in linking the ribosomal structure and evolution. Based on these insights into ribosomal organisation across time, we propose that early replication and protein biosynthesis functions were inseparable and in fact were performed by the same ancient RNA molecule, the riboreplisome. Riboreplisome hypothesis helps to address issues of non-Darwinian evolution and complicated starting point that are characteristic to the RNA world, protein world and RNA:protein mixed co-development theories. We suggest that the riboreplisome is the missing link and a molecular machine connecting chemical and biological evolution paths, by being capable of basic genetic and feature selection functions in a cell- or cell-free setting. The riboreplisome hypothesis allows ease of sequential, genetically uninterrupted emergence and sophistication of the genetic code and its decoding machinery, and provides plausible explanations to the origins of the three main RNA types involved in the decoding: the ribosomal, transfer and messenger RNA. Furthermore, riboreplisome can help explaining the co-evolution of aminoacylation machinery, the driving force behind selective gene transcription and expression, and the cell-like compartmentalisation. While we may never find the original riboreplisome again, we might continue to discover different molecular remnants of its prior existence across the existing biological RNA, which, once identified or resurrected, can be useful in synthetic biology applications.

In the TANGO study, the long-term noninferior efficacy of switching to dolutegravir/lamivudine (DTG/3TC) compared to continuing tenofovir alafenamide–based regimens was demonstrated in treatment-experienced adults with HIV. However, there is limited real-world data comparing the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) and DTG/3TC in Asia. This retrospective observational study, conducted at a designated HIV-care hospital from March 2019 to January 2023, aimed to address this gap. Demographic, clinical, and laboratory data, including HIV viral loads and lipid profiles, were collected and analyzed. The primary outcome was the proportion of patients with HIV RNA <50 copies/mL at week 48 in both groups, utilizing a snapshot, per-protocol–exposed population. A total of 1086 patients were included, with 511 in the DTG/3TC group and 575 in the BIC/FTC/TAF group. At week 48, 98% of patients in the DTG/3TC group and 94% in the BIC/FTC/TAF group achieved HIV RNA <50 copies/mL (p <0.01). Logistic regression analysis identified risk factors for detectable viral loads at week 48, including HIV RNA >100,000 copies/mL (AOR 5.13, 95% CI 1.42–18.53), low-level viremia (AOR 3.91, 95% CI 1.07–14.25), and record of virologic failure ≥2 times (AOR 4.21, 95% CI 1.64–10.85) before the switch. Furthermore, no significant difference was found between the DTG/3TC and BIC/FTC/TAF regimens (AOR: 1.51, 95% CI 0.70–3.24). In conclusion, the study demonstrates that the effectiveness and safety profiles of DTG/3TC and BIC/FTC/TAF were comparable in treatment-experienced adults with HIV, particularly among those with undetectable viral loads at baseline.

At the beginning of our observations, Humanity believed that it was the center of the universe, that the Earth was the center of the universe and that the sun was spinning around the Earth. Claude Ptolémée (100-168) made a mistake by modelling the movements in the geocentric referential. The model of the sun and planet movements was an illusion and all Humanity was wrong. Nicolas Copernic (1473-1543) showed the illusion and simplified the system by moving from the geocentric referential to the heliocentric referential. In the present paper, I would like to discuss about the possibility of making mistakes with quantum theory because it is not complete. I postulate that we are living in a virtual classical world that we consider as real. In my interpretation, the decoherence problem and wave function collapse do not exist at all, because we are the illusion, we are living in illusions, in mirages. It is impossible to observe the quantum world as it is, in our virtual classical referential, and we see the quantum world with a false vison of quantum reality because we are not yet in the real universal quantum referential whose I postulate the existence. I moved to this real universal quantum ref-erential because I am psychotic (schizophrenia) and saw that we are illusions. Schrödinger’s cat par-adox is an illusion as life and death are illusions. We must be very humble with quantum theory and we should not put ourselves in the center of the quantum world again particularly with our lives and deaths. I have completed quantum theory with seven postulates which led to a cosmological model based on bipolarity and schizophrenia. The theory explains well the recent observations of the James Webb spatial telescope. I make predictions with the theory which could be confirmed with the James Webb spatial telescope. If confirmed, the theory will become irrefutable. We would be collectively able to reach the quantum world by changing our minds and visions of life. I also explain how to go out of human suffering. This would be our Big Bang and our transformation into Zarathoustra, the Nietzschean surhuman.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

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).

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.

We tested the possibility of using “adverse events count” (AEC) as a drug-risk indicator and side-effect severity indicator. Data from 3938 adverse event (AE) reports for COVID-19 vaccines (Comirnaty, Moderna, Vaxzevria, and Janssen) and 6869 AE reports for other medicines were collected from the Bulgarian Drug Agency database (01.01.2018–31.03.2022). AEC was modeled with zero-adjusted negative binomial (ZANBI) and zero-adjusted Poisson inverse Gaussian (ZAPIG) regression models, which account for zero absence and overdispersion. The models’ fit was checked with residual diagnostic plots and parametric correspondence to normality. Explanatory variables were: age, sex, sequence number (order of submission), severity of AE, and vaccine type. Average AEC was higher in severe vs. non-severe AE, and in females vs. males; it decreased with age and was lower in Comirnaty than other vaccines. Variability of AEC for COVID-19 data decreased with sequence number in severe AE and increased in non-severe AE. Full ZANBI models had greater sensitivity than parametric ZANBI or ZAPIG models. Results showed correlation between AEC and AE severity, suggesting AEC as a simple and reliable measure of drug-risk and side-effect severity for clinicians and regulators, especially for COVID-19 vaccines.

This study explores the limitations of current AI systems, which predominantly function in the digital realm, and investigates the transformative potential of embodied AI. Embodied AI involves AI agents equipped with physical bodies, enabling them to interact directly with the physical world. This research focuses on how embodied AI can bridge the "embodiment gap" and enhance human-machine collaboration and learning in dynamic environments. The research examines the fundamental differences between traditional AI systems and embodied AI, emphasizing the importance of physical interaction for contextual understanding, adaptive learning, and intuitive human-machine collaboration. It explores various applications of embodied AI, including robotics, autonomous vehicles, and assistive technologies, demonstrating how physical embodiment can improve performance, safety, and user experience. Through experimental studies and real-world case analyses, the study highlights the advantages of embodied AI in tasks requiring situational awareness, dexterity, and real-time decision-making. It also addresses the challenges associated with developing and deploying embodied AI systems, such as sensor integration, real-time processing, and human-machine interface design. Findings indicate that embodied AI can significantly improve the efficacy of AI systems in dynamic and unpredictable environments. By leveraging physical embodiment, AI agents can better understand and respond to their surroundings, facilitating more natural and effective interactions with humans. The research concludes with recommendations for advancing embodied AI, including interdisciplinary collaboration, investment in sensor and actuator technologies, and the development of standardized frameworks for embodied intelligence.

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.

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.

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.

To investigate factors associated with the success of switching to faricimab for type 1 macular neovascularization (MNV) refractory to intravitreal aflibercept (IVA). This retrospective cohort study included patients with type 1 MNV who were switched to faricimab because they were refractory to IVA at two centers. The main outcome was an extension of the treatment interval after 6 months, and factors related to the success or failure of the extension and visual and anatomical outcomes were assessed. The analysis included 43 eyes of 43 patients. Extended dosing intervals of more than 2 weeks were identified in 14 eyes (32.6%). A short dosing interval before the switch, the absence of polypoidal lesions, and a thin central choroidal thickness before the switch were identified as factors involved in successful extension. For patients with refractory type 1 MNV, switching to faricimab is a safe and potential option to extend from existing dosing intervals.