The effect of consumer-perceived COVID-19 ad value on health-protective behavior: Mediating role of engagement.

Though the pandemic has passed, social media-based messaging continues to exhibit COVID-19-related cues (e.g., wearing a face mask to stay safe), continuing to foster consumers' health-protective behavior. However, it remains unclear how social media communications (e.g., advertising) affect such behavior, exposing an important literature-based gap. Addressing this gap, we deploy Ducoffe's advertising value model to examine how pandemic-related advertisements (e.g., those urging consumers to stay safe, including post-the pandemic) impact their health-protective behavior. We also examine how consumer engagement (CE) mediates these associations. To explore these issues, we collected data from a sample of 301 Gen Z consumers, which was analyzed using partial least squares structural equation modeling (PLS-SEM). We find that informative, credible, irritating, and obtrusive ads raise consumer engagement and health-protective behavior. Engagement was also found to strengthen these associations, revealing their strategic value. We conclude by outlining important theoretical and practical implications that arise from our analyses.

Unraveling the genetic variations underlying virulence disparities among SARS-CoV-2 strains across global regions: insights from Pakistan.

Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants have emerged that may exhibit different etiological effects such as enhanced transmissibility and infectivity. However, genetic variations that reduce virulence and deteriorate viral fitness have not yet been thoroughly investigated. The present study sought to evaluate the effects of viral genetic makeup on COVID-19 epidemiology in Pakistan, where the infectivity and mortality rate was comparatively lower than other countries during the first pandemic wave. For this purpose, we focused on the comparative analyses of 7096 amino-acid long polyprotein pp1ab. Comparative sequence analysis of 203 SARS-CoV-2 genomes, sampled from Pakistan during the first wave of the pandemic revealed 179 amino acid substitutions in pp1ab. Within this set, 38 substitutions were identified within the Nsp3 region of the pp1ab polyprotein. Structural and biophysical analysis of proteins revealed that amino acid variations within Nsp3's macrodomains induced conformational changes and modified protein-ligand interactions, consequently diminishing the virulence and fitness of SARS-CoV-2. Additionally, the epistatic effects resulting from evolutionary substitutions in SARS-CoV-2 proteins may have unnoticed implications for reducing disease burden. In light of these findings, further characterization of such deleterious SARS-CoV-2 mutations will not only aid in identifying potential therapeutic targets but will also provide a roadmap for maintaining vigilance against the genetic variability of diverse SARS-CoV-2 strains circulating globally. Furthermore, these insights empower us to more effectively manage and respond to potential viral-based pandemic outbreaks of a similar nature in the future.

Cis-regulatory control of mammalian Trps1 gene expression.

TRPS1 serves as the causative gene for tricho-rhino phalangeal syndrome, known for its craniofacial and skeletal abnormalities. The Trps1 gene encodes a protein that represses Wnt signaling through strong interactions with Wnt signaling inhibitors. The identification of genomic cis-acting regulatory sequences governing Trps1 expression is crucial for understanding its role in embryogenesis. Nevertheless, to date, no investigations have been conducted concerning these aspects of Trps1. To identify deeply conserved noncoding elements (CNEs) within the Trps1 locus, we employed a comparative genomics approach, utilizing slowly evolving fish such as coelacanth and spotted gar. These analyses resulted in the identification of eight CNEs in the intronic region of the Trps1 gene. Functional characterization of these CNEs in zebrafish revealed their regulatory potential in various tissues, including pectoral fins, heart, and pharyngeal arches. RNA in-situ hybridization experiments revealed concordance between the reporter expression pattern induced by the identified set of CNEs and the spatial expression pattern of the trps1 gene in zebrafish. Comparative in vivo data from zebrafish and mice for CNE7/hs919 revealed conserved functions of these enhancers. Each of these eight CNEs was further investigated in cell line-based reporter assays, revealing their repressive potential. Taken together, in vivo and in vitro assays suggest a context-dependent dual functionality for the identified set of Trps1-associated CNE enhancers. This functionally characterized set of CNE-enhancers will contribute to a more comprehensive understanding of the developmental roles of Trps1 and can aid in the identification of noncoding DNA variants associated with human diseases.

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals.

Abnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis-regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15-21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage-specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co-option of limb specificity from other tissues prior to the divergence of amniotes and lobe-finned fish. These results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.

Non-Markovian Modeling of Nonequilibrium Fluctuations and Dissipation in Active Viscoelastic Biomatter.

Based on a Hamiltonian that incorporates the elastic coupling between a tracer particle and the embedding active viscoelastic biomatter, we derive a generalized non-Markovian Langevin model for the nonequilibrium mechanical tracer response. Our analytical expressions for the frequency-dependent tracer response function and the tracer positional autocorrelation function agree quantitatively with experimental data for red blood cells and actomyosin networks with and without adenosine triphosphate over the entire frequency range and in particular reproduce the low-frequency violation of the fluctuation-dissipation theorem. The viscoelastic power laws, the elastic constants and effective friction coefficients extracted from the experimental data allow straightforward physical interpretation.

Challenges and Prospective of Enhancing Hydatid Cyst Chemotherapy by Nanotechnology and the Future of Nanobiosensors for Diagnosis.

Hydatid cysts have been widely recognized for decades as a common medical problem that affects millions of people. A revolution in medical treatment may be on the prospect of nanotechnology enhancing chemotherapy against hydatid cysts. An overview of nanotechnology's impact on chemotherapeutics is presented in the current review. It discusses some of the challenges as well as some of the opportunities. The application of nanotechnology to enhance chemotherapy against hydatid cysts is what this review will explore. Nanotechnology is a critical component of delivering therapeutic agents with greater precision and efficiency and targeting hydatid cysts with better efficacy, and minimizing interference with surrounding tissue. However, there are biodistribution challenges, toxicity, and resistance problems associated with nanotherapeutics. Additionally, nanobiosensors are being investigated to enable the early diagnosis of hydatid cysts. A nanobiosensor can detect hydatid cysts by catching them early, non-invasively, rapidly, and accurately. The sensitivity and specificity of diagnostic tests can be enhanced with nanobiosensors because they take advantage of the unique properties of nanomaterials. By providing more precise and customized treatment options for hydatid cysts, nanotechnology may improve therapeutic options and strategies for diagnosing the disease. In conclusion, treatment with nanotechnology to treat hydatid cysts is potentially effective but presents many obstacles. Furthermore, nanobiosensors are being integrated into diagnostic techniques, as well as helping to diagnose patients earlier and more accurately.

Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions.

BACKGROUND: Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation. RESULTS: To start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele. CONCLUSION: These results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might. have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution. METHODS: The present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches.

Database Commons: A Catalog of Worldwide Biological Databases.

Biological databases serve as a global fundamental infrastructure for the worldwide scientific community, which dramatically aid the transformation of big data into knowledge discovery and drive significant innovations in a wide range of research fields. Given the rapid data production, biological databases continue to increase in size and importance. To build a catalog of worldwide biological databases, therefore, we curate a total of 5825 biological databases from 8931 publications, which are geographically distributed in 72 countries/regions and developed by 1975 institutions (as of September 20, 2022). We further devise a z-index, a novel index to characterize the scientific impact of a database, and rank all these biological databases as well as their hosting institutions and countries in terms of citation and z-index. Consequently, we present a series of statistics and trends of worldwide biological databases, yielding a global perspective to better understand their status and impact for life and health sciences. An up-to-date catalog of worldwide biological databases as well as their curated meta-information and derived statistics is publicly available at Database Commons (https://ngdc.cncb.ac.cn/databasecommons/).

Interpreting the impact of extraversion and neuroticism on social media addiction among university students of Pakistan: A mediated and moderated model.

This study aims to investigate the association between two important personality traits (extraversion and neuroticism) and social media addiction (SMA) through social media usage (SMU) while considering the important moderating role of life satisfaction. We collected data from 623 university students in Pakistan through an electronic survey. SmartPLS software was utilized to perform partial least squares - structural equation modeling (PLS-SEM) analyses to verify our proposed model. The results revealed a significant direct association between extraversion and social media addiction whereas social media usage partially mediates this relationship. However, the direct relationship between neuroticism and social media addiction was not found significant but was fully mediated by social media usage. In addition, life satisfaction revealed no moderating effect on the relationship between extraversion, neuroticism, and social media addiction. Our results contribute to the prior studies that intensity of using social media for whatever purpose leads to social media addiction; life satisfaction does not play any role in social media addiction. Limitations and directions for future research are discussed.

The effect of three violent videogame engagement states on aggressive behavior: A partial least squares structural equation modeling approach.

Debate on violent games and their effect on aggressive behavior remains inconclusive. This study aims to study the predicting role of cognitive, affective, and behavioral engagement states in violent videogames on aggressive behavior, which remains nebulous to date. We visited gaming zones and administered the study survey to collect data from violent videogame users. We collected 208 valid responses that were further analyzed. The present study used SmartPLS (3.3.3) software to perform partial least squares structural equation modeling (PLS-SEM) analysis in two stages. In the first stage, the measurement model assessment reported that cognitive, affective, behavioral, and aggressive behavior proved to be reliable reflective-formative composite constructs. Whereas, the second phase illustrated that cognitive engagement in violent videogames fails to impact aggressive behavior. The other two engagement states (affective and behavioral) in violent games showed a positive impact on aggressive behavior. Our study contributes to aggressive behavior literature by understanding how violent videogame engagement states impact aggressive behavior, which is crucial to recognize aggression so that steps can be taken toward addressing it. This study also contributes methodologically by utilizing the hierarchical component model (HCM) approach to estimate, specify, and validate the hierarchical structure of higher-order constructs (i.e., consumer violent videogame engagement dimensions (cognitive, affective, and behavioral) and aggressive behavior) as reflective-formative composite models.

Investigating male gamers' behavioral intention to play PUBG: Insights from playful-consumption experiences.

This research investigates the factors that affect male gamers' behavioral intention to play PlayerUnknown's Battlegrounds (PUBG), which is one of the most widely played online games of today's era. We examine the factors through the lens of the hedonic consumption model (i.e., playful-consumption experiences) and use the gratification theory to predict behavioral intention to play PUBG. Data from 248 male PUBG gamers were analyzed using PLS-SEM analyses. The study involved an initial stage where an estimation model (i.e., measurement model) was analyzed to assess the constructs' reliability and validity. Following this, the second stage involved assessing the theoretical model to test the relationship between the principle constructs. The study found that playful-consumption experience factors, such as escapism, emotional involvement, sensory experience, enjoyment, and arousal, significantly influenced the behavioral intentions to play PUBG. The research findings further indicate that role-projection and fantasy failed to impact consumers' intention to play PUBG. This study provides both theoretical and practical implications. It fills the literature gap by focusing on predicting the behavioral intention to play PUBG through the playful-consumption experiences of a popular online multiplayer game. Practically, this study could potentially open avenues for gaming companies to address how different playful-consumption experiences impact game users' behavioral intentions.

Interventions to Improve the Willingness to Work Among Health care Professionals in Times of Disaster: A Scoping Review.

The critical role of the health workforce in the function of the health care system is undeniable. In times of disaster and public health emergency, the importance of this valuable resource for the organization multiplies. This scoping review was conducted to identify, analyze, and categorize interventions to improve willingness to work in times of disaster as well as the existing knowledge gaps in the topic. For this purpose, four databases were searched. These included Scopus, PubMed, WOS, and World Health Organization observatory, and they were searched for papers published from July 2000 to September 2020. Studies of the English language that described strategies to improve human resources for health willingness to work during times of disaster/public health emergency were included. Full-text papers were screened by authors and data extraction was done according to self-designed form. Framework analysis identified key interventions based on human resources for health action framework. From 6246 search results, 52 articles were included, a great portion of which was published in 2020 probably due to the COVID-19 pandemic. Northern America was the region with most studies. From 52 included studies, 21 papers have reported the interventions to improve willingness to work and 31 papers have explored factors that affected a willingness to work. The interventions used in the studies were categorized into five themes as Leadership, Partnership, Financing, Education, and Organizational policies. The most and least interventions were financial and partnership respectively. The review identified a wide range of feasible strategies and interventions to improve human resources for health's willingness to work at times of disaster that are expected to be effective. Organizations should let the staff know these decisions and as a necessary step in every organizational intervention remember to evaluate the impacts.

Predicting Video Game Addiction Through the Dimensions of Consumer Video Game Engagement: Quantitative and Cross-sectional Study.

BACKGROUND: Video games are expanding exponentially with their increased popularity among users. However, this popularity has also led to an increase in reported video game addiction. There may be consumer engagement-related factors that may influence video game addiction. OBJECTIVE: This study aims to empirically examine the impact of the dimensions of consumer video game engagement on video game addiction. The dimensions are dedication, absorption, conscious attention, social connection, enthusiasm, and interaction. We utilize the uses and gratifications theory to study the video game engagement dimensions as potential factors through which gamers feel gratified and engaged in video game playing. Additionally, this study incorporates the cultivation theory to investigate how video game engagement factors trigger video game addiction. METHODS: A two-step process was applied for data analysis on valid cases of 176 gamers aged 15-25 years: video game addiction was specified and validated as a reflective-formative construct, and hypothesis testing was later performed using the WarpPLS on valid respondents. RESULTS: The analysis uncovered 2 dimensions of video game engagement: social connection with P=.08 and interaction with P=.49, which did not significantly contribute to video game addiction. CONCLUSIONS: This study offers unique insights to a myriad of stakeholders, mostly psychologists and psychiatrists, who routinely prescribe behavior modification techniques to treat video game addiction.

Genomic Epidemiology of SARS-CoV-2 in Pakistan.

COVID-19 has swept globally and Pakistan is no exception. To investigate the initial introductions and transmissions of the SARS-CoV-2 in Pakistan, we performed the largest genomic epidemiology study of COVID-19 in Pakistan and generated 150 complete SARS-CoV-2 genome sequences from samples collected from March 16 to June 1, 2020. We identified a total of 347 mutated positions, 31 of which were over-represented in Pakistan. Meanwhile, we found over 1000 intra-host single-nucleotide variants (iSNVs). Several of them occurred concurrently, indicating possible interactions among them or coevolution. Some of the high-frequency iSNVs in Pakistan were not observed in the global population, suggesting strong purifying selections. The genomic epidemiology revealed five distinctive spreading clusters. The largest cluster consisted of 74 viruses which were derived from different geographic locations of Pakistan and formed a deep hierarchical structure, indicating an extensive and persistent nation-wide transmission of the virus that was probably attributed to a signature mutation (G8371T in ORF1ab) of this cluster. Furthermore, 28 putative international introductions were identified, several of which are consistent with the epidemiological investigations. In all, this study has inferred the possible pathways of introductions and transmissions of SARS-CoV-2 in Pakistan, which could aid ongoing and future viral surveillance and COVID-19 control.

Prevalence and Associated Factors of Problematic Smartphone Use During the COVID-19 Pandemic: A Bangladeshi Study.

BACKGROUND: Problematic smartphone use (PSU) has been increasing hastily in recent decades, and it has become inseparable during the COVID-19 pandemic, especially among the students who are at risk of problematic smartphone use. Therefore, the present study aimed to investigate the prevalence and associated factors of PSU during the COVID-19 pandemic among the Bangladeshi students. METHODS: A total of 601 Bangladeshi students were recruited through an online-based cross-sectional survey that was conducted between October 7 and November 2, 2020. The survey collected information related to socio-demographics, behavioral health, internet use behaviors, depression, anxiety, and PSU. Independent samples t-test and one-way ANOVA were performed to present the relationship between the studied variables and PSU. Multiple linear regression analysis was also used for investigating the explanatory power of the predictive models for PSU. RESULTS: Surprisingly, about 86.9% of the students scored to be problematic smartphone users (≥21 out of a total 36 based on the Smartphone Application-Based Addiction Scale). In addition, medical students, engaging in a relationship, performing less physical activity, longer duration of internet use, some sorts of internet use purpose (eg, messaging, watching videos, using social media), depression, and anxiety were significantly associated with higher scores of PSU. After adjusting all the studied variables, the final model explained a 31.3% variance predicting PSU. CONCLUSION: The present study is one of the first approaches to assess the prevalence of PSU among the Bangladeshi students during the COVID-19 pandemic, whereas the addiction level was superfluous (and this may be due to more online engagement related to the pandemic). Thus, the study recommended strategies or policies related to the students' risk-reducing and healthy use of smartphones.

Molecular evolutionary analysis of human primary microcephaly genes.

BACKGROUND: There has been a rapid increase in the brain size relative to body size during mammalian evolutionary history. In particular, the enlarged and globular brain is the most distinctive anatomical feature of modern humans that set us apart from other extinct and extant primate species. Genetic basis of large brain size in modern humans has largely remained enigmatic. Genes associated with the pathological reduction of brain size (primary microcephaly-MCPH) have the characteristics and functions to be considered ideal candidates to unravel the genetic basis of evolutionary enlargement of human brain size. For instance, the brain size of microcephaly patients is similar to the brain size of Pan troglodyte and the very early hominids like the Sahelanthropus tchadensis and Australopithecus afarensis. RESULTS: The present study investigates the molecular evolutionary history of subset of autosomal recessive primary microcephaly (MCPH) genes; CEP135, ZNF335, PHC1, SASS6, CDK6, MFSD2A, CIT, and KIF14 across 48 mammalian species. Codon based substitutions site analysis indicated that ZNF335, SASS6, CIT, and KIF14 have experienced positive selection in eutherian evolutionary history. Estimation of divergent selection pressure revealed that almost all of the MCPH genes analyzed in the present study have maintained their functions throughout the history of placental mammals. Contrary to our expectations, human-specific adoptive evolution was not detected for any of the MCPH genes analyzed in the present study. CONCLUSION: Based on these data it can be inferred that protein-coding sequence of MCPH genes might not be the sole determinant of increase in relative brain size during primate evolutionary history.

Molecular signatures of selection on the human GLI3 associated central nervous system specific enhancers.

The zinc finger-containing transcription factor Gli3 is a key mediator of Hedgehog (Hh) signaling pathway. In vertebrates, Gli3 has widespread expression pattern during early embryonic development. Along the anteroposterior axes of the central nervous system (CNS), dorsoventral neural pattern elaboration is achieved through Hh mediated spatio-temporal deployment of Gli3 transcripts. Previously, we and others uncovered a set of enhancers that mediate many of the known aspects of Gli3 expression during neurogenesis. However, the potential role of Gli3 associated enhancers in trait evolution has not yet received any significant attention. Here, we investigate the evolutionary patterns of Gli3 associated CNS-specific enhancers that have been reported so far. A subset of these enhancers has undergone an accelerated rate of molecular evolution in the human lineage in comparison to other primates/mammals. These fast-evolving enhancers have acquired human-specific changes in transcription factor binding sites (TFBSs). These human-unique changes within subset of Gli3 associated CNS-specific enhancers were further validated as single nucleotide polymorphisms through 1000 Genome Project Phase 3 data. This work not only infers the molecular evolutionary patterns of Gli3 associated enhancers but also provides clues for putative genetic basis of the population-specificity of gene expression regulation.

Comparative genomic analysis of human GLI2 locus using slowly evolving fish revealed the ancestral gnathostome set of early developmental enhancers.

BACKGROUND: The zinc finger-containing transcription factor Gli2, is a key mediator of Hedgehog (Hh) signaling and participates in embryonic patterning of various organs including the central nervous system (CNS) and limbs. Abnormal expression of Gli2 can impede the transcription of Hh target genes through disruption of proper balance between Gli2 and Gli3 functions. Therefore, delineation of enhancers that are required for complementary roles of Glis would allow the interrogation of those pathogenic variants that cause gene dysregulation, and a corresponding abnormal phenotype. Previously, we reported tissue-specific enhancers for Gli family including Gli2 through direct tetrapod-teleost comparisons. RESULTS: Here, we employed the sequence alignments of slowly evolving spotted gar and elephant shark and have identified six novel conserved noncoding elements in human GLI2 containing locus. Zebrafish-based transgenic assays revealed that combined action of these autonomous CNEs reflects many aspects of Gli2 specific endogenous transcriptional activity, including CNS and pectoral fins. CONCLUSION: Taken together with our previous findings, this study suggests that Hh-signaling controlled deployment of Gli2 activity in embryonic patterning arose in the common ancestor of gnathostomes. These GLI2 specific cis-regulatory modules will help to identify DNA variants that probably reside outside of coding intervals and are associated with congenital anomalies.

Effect of deep transfer and multi-task learning on sperm abnormality detection.

Analyzing the abnormality of morphological characteristics of male human sperm has been studied for a long time mainly because it has many implications on the male infertility problem, which accounts for approximately half of the infertility problems in the world. Yet, detecting such abnormalities by embryologists has several downsides. To clarify, analyzing sperms through visual inspection of an expert embryologist is a highly subjective and biased process. Furthermore, it takes much time for a specialist to make a diagnosis. Hence, in this paper, we proposed two deep learning algorithms that are able to automate this process. The first algorithm uses a network-based deep transfer learning approach, while the second technique, named Deep Multi-task Transfer Learning (DMTL), employs a novel combination of network-based deep transfer learning and multi-task learning to classify sperm's head, vacuole, and acrosome as either normal or abnormal. This DMTL technique is capable of classifying all the aforementioned parts of the sperm in a single prediction. Moreover, this is the first time that the concept of multi-task learning has been introduced to the field of Sperm Morphology Analysis (SMA). To benchmark our algorithms, we employed a freely-available SMA dataset named MHSMA. During our experiments, our algorithms reached the state-of-the-art results on the accuracy, precision, and f0.5, as well as other important metrics, such as the Matthews Correlation Coefficient on one, two, or all three labels. Notably, our algorithms increased the accuracy of the head, acrosome, and vacuole by 6.66%, 3.00%, and 1.33%, and reached the accuracy of 84.00%, 80.66%, and 94.00% on these labels, respectively. Consequently, our algorithms can be used in health institutions, such as fertility clinics, with further recommendations to practically improve the performance of our algorithms.

Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition the secondary structural elements to create new intra-protein contacts and, thereby, may enhance the ability of SARS-CoV-2 to inhibit host immunity. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection-driven epistasis in protein evolution. Our findings warrant further characterization of macrodomain-specific evolutionary substitutions in in vitro and in vivo models to determine their inhibitory effects on the host immune system.