Influence of heat sintering on the physical properties of bulk La0.67Ca0.33MnO3 perovskite manganite: role of oxygen in tuning the magnetocaloric response.

The effect of heat treatments on bulk poly-crystalline La0.67Ca0.33MnO3 perovskite manganite is presented, to explore the possible enhancement in magnetocaloric performance. Samples were prepared via conventional solid-state reaction route with annealing and sintering at various temperatures. Detailed measurements of temperature-dependent and field-dependent magnetization were carried out to estimate the Curie point and order of magnetic transition. The increased sintering temperature results in a steep transition near the TC, and establishes the magnetic sensitivity as well as the active zone for substantial magnetocaloric performance, at about 168.2% for the LCM9 (sintered at 900 °C) sample. The cause for the significant improvement in the magnetic and magnetocaloric response is brought to light using detailed X-ray photoelectron spectroscopy (XPS) analysis, highlighting the role of oxygen in modifying the Mn3+/Mn4+ charge ratio. The maximum value of the isothermal magnetic entropy change for the optimized sample is found to be 6.4 J kg-1 K-1, achieved at 269 K, while temperature-averaged entropy change (TEC) values, TEC(ΔTH-C = 3 K) and TEC(ΔTH-C = 5 K), of 6 J kg-1 K-1 and 5.2 J kg-1 K-1, respectively, were obtained with a low magnetic field change of 20 kOe. The obtained isothermal entropy change at low field for the optimized La0.67Ca0.33MnO3 sample is higher than that of pure Gd and most oxide-based materials. The relative cooling power (RCP) value is around 93 J kg-1 (ΔH = 20 kOe). The order of the phase transition is examined with universal scaling; the scaled entropy change curves confirm the collapse onto a single curve for LCM9, asserting second-order character, whereas the breakdown of the curve with a dispersion relation (d) of 101.1% at Θ = -5 confirms the onset of intrinsic first-order nature in the case of the high-temperature-sintered samples. Calorimetry measurements show thermal hysteresis of 2.4 K and 7.1 K for LCM11 (sintered at 1100 °C) at ramp rates of 5 K min-1 and 10 K min-1, respectively, confirming the first-order nature of the magnetic transition.

Characterisation of Indian gut microbiome for B-vitamin production and its comparison with Chinese cohort.

The human gut microbiota can biosynthesize essential micronutrients such as B-vitamins and is also known for its metabolic cooperative behaviour. The present study characterises such B-vitamin biosynthesizers, their biosynthetic pathways, explores their prevalence and abundance, examines how lifestyle or diet affects them in multiple Indian cohorts and compares it with the Chinese cohort. To achieve this, publicly available faecal metagenome data of healthy individuals from multiple Indian (two urban and three tribal populations) and a Chinese cohort were analysed. The distribution of prevalence and abundance of B-vitamin biosynthesizers showed similar profiles to that of the entire gut community of the Indian cohort, and there were 28 B-vitamin biosynthesizers that had modest or higher prevalence and abundance. The omnivorous diet affected only the prevalence of a few B-vitamin biosynthesizers; however, lifestyle and/or location affected both prevalence and abundance. A comparison with the Chinese cohort showed that fourteen B-vitamin biosynthesizers were significantly more prevalent and abundant in Chinese as compared with Indian samples (False Discovery Rate (FDR) <= 0·05). The metabolic potential of the entire gut community for B-vitamin production showed that within India, the tribal cohort has a higher abundance of B-vitamin biosynthesis pathways as compared with two urban cohorts namely, Bhopal and Kasargod, and comparison with the Chinese cohort revealed a higher abundance in the latter group. Potential metabolic cooperative behaviour of the Indian gut microbiome for biosynthesis of the B-vitamins showed multiple pairs of species showed theoretical complementarity for complete biosynthetic pathways genes of thiamine, riboflavin, niacin and pantothenate.

Mandibular ramus- An indicator for gender determination: A digital panoramic study in Bagalkot population.

Background: In medico-legal investigations identification of skeletal remains is of utmost importance. The skeletal remains most commonly investigated are pelvic and skull bones with the mandible an important element to analyze sexual dimorphism. Mandibular ramus can differentiate between the two genders as the stages of mandibular development, growth rates, and duration are different in both genders. Metric analysis on the radiographs is found to be of higher values when skeletal sex determination is considered. Aims and Objectives: 1) To compare and evaluate the various measurements of the mandibular ramus on digital OPG's. 2) To assess the usefulness of mandibular ramus as an aid in gender determination in the Bagalkot population. Materials and Methods: A retrospective study was conducted on 80 patients (40 males & 40 females) using Kodak 8000 C digital panoramic radiographs of the Bagalkot population with ages ranging from 18 to 58 years. Five parameters namely coronoid ramus height, condyle ramus height, condyle coronoid breadth, maximum ramus breadth, and minimum ramus breadth were taken into consideration, the values were measured and data were analyzed. Statistical analysis was done using SPSS software. Results: In the present study, all the measurements of the mandibular ramus on digital panoramic radiographs showed a statistically significant difference between both the genders except for minimum ramus breadth which was found to be insignificant. Conclusion: Discriminant analysis of mandibular ramus using panoramic radiography can be used as an effective tool in gender determination and can be used as an aid in forensic sciences.

Retraction: Investigation on corrosion protection and mechanical performance of minerals substituted hydroxyapatite coating on HELCDEB-treated titanium using pulsed electrodeposition method.

[This retracts the article DOI: 10.1039/C4RA04484C.].

Congenital Transmesenteric Hernia - A Rare Presentation.

Congenital transmesenteric defect is a rare but serious condition which presents a diagnostic challenge as symptoms and investigations are nonspecific. Here, we present a case with fetal ascites and dilated bowel loops who underwent intervention within 6 h of birth. Laparotomy showed volvulus and gangrene of 45 cm of the distal ileum, which was herniating through mesenteric defect. Timely detection and intervention can help in preventing significant morbidity and mortality. Given the downside to delay of surgical intervention and lack of specific tests, open exploration continues to be the only way to establish a definitive diagnosis of a transmesenteric hernia.

The translating bacterial ribosome at 1.55 Å resolution generated by cryo-EM imaging services.

Our understanding of protein synthesis has been conceptualised around the structure and function of the bacterial ribosome. This complex macromolecular machine is the target of important antimicrobial drugs, an integral line of defence against infectious diseases. Here, we describe how open access to cryo-electron microscopy facilities combined with bespoke user support enabled structural determination of the translating ribosome from Escherichia coli at 1.55 Å resolution. The obtained structures allow for direct determination of the rRNA sequence to identify ribosome polymorphism sites in the E. coli strain used in this study and enable interpretation of the ribosomal active and peripheral sites at unprecedented resolution. This includes scarcely populated chimeric hybrid states of the ribosome engaged in several tRNA translocation steps resolved at ~2 Å resolution. The current map not only improves our understanding of protein synthesis but also allows for more precise structure-based drug design of antibiotics to tackle rising bacterial resistance.

A methodological analysis of CTRI registered clinical trials on ayurveda interventions for COVID-19 management.

BACKGROUND: Clinical trial protocols provide important methodological information and are expected to be detailed. During COVID-19 pandemic several studies has been registered on CTRI regarding ayurveda for COVID-19. However, there is accumulating evidence that many protocols do not address important study elements. Therefore it is critical to analyze the clinical trial protocols and methodology of ayurveda clinical trials regarding COVID-19 registered on CTRI. OBJECTIVE: To assess the methodological aspects of CTRI registered ayurveda trial for COVID-19, based upon available trial protocols, during 2020 and 2021. MATERIALS AND METHODS: We searched the CTRI database for interventional trials protocols regarding ayurveda for COVID-19, during the year 2020 and 2021. We assessed the protocols for several methodological aspects such as study design, sample size, randomization, blinding, intervention (duration and type) and outcomes. RESULTS: Total 140 clinical trial protocols were analyzed. The highest numbers of studies were registered in May, June, and July 2020 with steady decline thereafter despite rising COVID-19 cases. Total 90 trials were randomized and only 29 are blinded, however majority of the trials did not mention methods of randomization and blinding. Sample size in hospital-based studies ranged from 30 -500 and in community-based studies from 500-80000, however, sample size calculation details were not mentioned in the protocol. Most common intervention used were guduchi, ashwagandha, yashtimadhu, AYUSH-64, curcumin and chyavanprash. CONCLUSION: Although there was a surge of clinical trials on CTRI regarding ayurveda for COVID -19, the methodological quality is not up to the mark with large scope for improvement.

A Prospective Comparative Study of the Functional Outcomes of Patellar Resurfacing Versus Non-resurfacing in Patients Undergoing Total Knee Arthroplasty.

Background and objective Total knee arthroplasty (TKA) is a highly successful surgical procedure. However, there is a lack of consensus about whether to resurface the patella or not. This study was aimed at evaluating the outcome of patellar resurfacing in terms of a decrease in the incidence of anterior knee pain after TKA and assessing whether patellar resurfacing is beneficial in improving functional outcomes. Materials and methods This prospective comparative study included 100 patients undergoing TKA who were randomly allotted to the patellar resurfacing or non-resurfacing group. Functional evaluation was done based on the Knee Society Score, and the pain was evaluated by the visual analogue scale (VAS) preoperatively and after one year. Results There was a significant improvement in the Knee Society scores as well as the pain scores in both groups postoperatively. The patellar resurfacing group showed statistically significant improvement as compared to the non-resurfacing group in the Knee Society clinical and functional scores as well as the VAS at the end of one year. Conclusion Patellar resurfacing during TKA provides better clinical and functional outcomes as well as more relief from anterior knee pain as compared to non-resurfacing of the patella.

AYURAKSHA, a prophylactic Ayurvedic immunity boosting kit reducing positivity percentage of IgG COVID-19 among frontline Indian Delhi police personnel: A non-randomized controlled intervention trial.

Objective: The world continues to face the COVID-19 crisis, and efforts are underway to integrate traditional medicine interventions for its effective management. The study aimed to determine the efficacy of the "AYURAKSHA" kit in terms of post-interventional percentage of COVID-19 IgG positivity, immunity levels, and quality of life (QoL) against COVID-19. Method: This was a non-randomized controlled, prospective intervention trial, done after the distribution of 80,000 AYURAKSHA kits (constituent of Sanshamani Vati, AYUSH Kadha, and Anu Taila) among Delhi police participants in India. Among 47,827 participants, the trial group (n = 101) was evaluated with the positivity percentage of IgG COVID-19 and Immune Status Questionnaire (ISQ) scores as a primary outcome and the WHO Quality of Life Brief Version (QOL BREF) scores along with hematological parameters as a secondary outcome in comparison to the control group (n = 71). Results: The data showed that the percentage of COVID-19 IgG positivity was significantly lower in the trial group (17.5 %) as compared to the control group (39.4 %, p = 0.003), indicating the lower risk (55.6%) of COVID-19 infection in the trial group. The decreased incidence (5.05%) and reduced mortality percentage (0.44%) of COVID-19 among Delhi police officers during peak times of the pandemic also corroborate our findings. The ISQ score and WHO-QOL BREF tool analysis showed the improved scores in the trial group when compared with the controls. Furthermore, no dysregulated blood profile and no increase in inflammation markers like C-reactive protein, erythrocyte sedimentation rate, Interleukin-6 (IL-6) were observed in the trial group. However, significantly enhanced (p = 0.027) IL-6 levels and random blood sugar levels were found in the control group (p = 0.032), compared to a trial group (p = 0.165) post-intervention. Importantly, the control group showed more significant (p = 0.0001) decline in lymphocyte subsets CD3+ (% change = 21.04), CD4+ (% change = 20.34) and CD8+ (% change = 21.54) levels than in trial group, confirming more severity of COVID-19 infection in the control group. Conclusion: The AYURAKSHA kit is associated with reduced COVID-19 positivity and with a better quality of life among the trial group. Hence, the study encourages in-depth research and future integration of traditional medicines for the prevention of the COVID-19 pandemic. Clinical trial registration: http://ctri.nic.in/, identifier: CTRI/2020/05/025171.

Fear, Stigma and Othering: The Impact of COVID-19 Rumours on Returnee Migrants and Muslim Populations of Nepal.

The paper explores how COVID-19-related moral panics have led to fear and othering practices among returnee Nepalese migrants from India and Muslims living in Nepal. This qualitative study included in-depth interviews with 15 returnee migrants, 15 Muslims from Kapilvastu and Banke districts of Nepal, and eight interviews with media and health professionals, and representatives from migration organisations. Four themes emerged from our data analysis: (1) rumours and mis/disinformation; (2) impact of rumours on marginalised groups (with three sub-themes: (i) perceived fear; (ii) othering practices; (iii) health and social impact); (3) resistance; and (4) institutional response against rumours. Findings suggest that rumours and misinformation were fuelled by various media platforms, especially social media (e.g., Facebook, YouTube) during the initial months of the lockdown. This created a moral panic which led to returnee migrants and Muslim populations experiencing fear and social isolation. Resistance and effective institutional responses to dispel rumours were limited. A key contribution of the paper is to highlight the lived experiences of COVID-19 related rumours on marginalised groups. The paper argues that there is a need for clear government action using health promotion messages to tackle rumours (health-related or otherwise), mis/disinformation and mitigating the consequences (hatred and tensions) at the community level.

Human peripheral blur is optimal for object recognition.

Our vision is sharpest at the centre of our gaze and becomes progressively blurry into the periphery. It is widely believed that this high foveal resolution evolved at the expense of peripheral acuity. But what if this sampling scheme is actually optimal for object recognition? To test this hypothesis, we trained deep neural networks on "foveated" images mimicking how our eyes sample the visual field: objects (wherever they were in the image) were sampled at high resolution, and their surroundings were sampled with decreasing resolution away from the objects. Remarkably, networks trained with the known human peripheral blur profile yielded the best performance compared to networks trained on shallower and steeper blur profiles, and compared to baseline state-of-the-art networks trained on full resolution images. This improvement, although slight, is noteworthy since the state-of-the-art networks are already trained to saturation on these datasets. When we tested human subjects on object categorization, their accuracy deteriorated only for steeper blur profiles, which is expected since they already have peripheral blur in their eyes. Taken together, our results suggest that blurry peripheral vision may have evolved to optimize object recognition rather than merely due to wiring constraints.

Invariant representation of physical stability in the human brain.

Successful engagement with the world requires the ability to predict what will happen next. Here, we investigate how the brain makes a fundamental prediction about the physical world: whether the situation in front of us is stable, and hence likely to stay the same, or unstable, and hence likely to change in the immediate future. Specifically, we ask if judgments of stability can be supported by the kinds of representations that have proven to be highly effective at visual object recognition in both machines and brains, or instead if the ability to determine the physical stability of natural scenes may require generative algorithms that simulate the physics of the world. To find out, we measured responses in both convolutional neural networks (CNNs) and the brain (using fMRI) to natural images of physically stable versus unstable scenarios. We find no evidence for generalizable representations of physical stability in either standard CNNs trained on visual object and scene classification (ImageNet), or in the human ventral visual pathway, which has long been implicated in the same process. However, in frontoparietal regions previously implicated in intuitive physical reasoning we find both scenario-invariant representations of physical stability, and higher univariate responses to unstable than stable scenes. These results demonstrate abstract representations of physical stability in the dorsal but not ventral pathway, consistent with the hypothesis that the computations underlying stability entail not just pattern classification but forward physical simulation.

Physiological significance of bistable circuit design in metabolic homeostasis: role of integrated insulin-glucagon signalling network.

BACKGROUND: Insulin and glucagon signalling pathways operate in a synchronised manner to regulate metabolic homeostasis in different physiological conditions (like postprandial, fasting & exercise). Non-linear positive feedback loops involving effector molecules such as AKT and PKA in anabolic and catabolic signalling modules have a key role in eliciting bistable response in these networks. METHODS: We have reviewed literature on insulin and glucagon signaling pathways in metabolic regulation along with the relevance of bistability in homeostasis. An ODE-based integrated signalling network model is used to simulate insulin and glucagon resistance conditions. Modifications in homeostatic to anabolic and catabolic switch activation thresholds are analyzed, indicating the effectiveness of insulin and glucagon signalling pathways in normal and diseased conditions. RESULTS: Perturbation analysis of the kinetic model provides valuable insights on bistability and its characterization with respect to endocrine inputs. Disturbance in bistability is linked with dysregulation of plasma macronutrient levels (glucose, fatty acids and amino acids) in abnormal conditions like insulin and glucagon resistance, which is associated with obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. CONCLUSIONS: This article highlights the role of Systems biology approach in explaining plausible mechanisms underlying metabolic abnormalities. It captures essential crosstalk and feedback mechanisms that play a key role in inducing bistable response in a variety of physiological situations, as well as hints at how to reverse insulin and glucagon resistance.

Improving Machine Vision Using Human Perceptual Representations: The Case of Planar Reflection Symmetry for Object Classification.

Achieving human-like visual abilities is a holy grail for machine vision, yet precisely how insights from human vision can improve machines has remained unclear. Here, we demonstrate two key conceptual advances: First, we show that most machine vision models are systematically different from human object perception. To do so, we collected a large dataset of perceptual distances between isolated objects in humans and asked whether these perceptual data can be predicted by many common machine vision algorithms. We found that while the best algorithms explain  âˆ¼ 70 percent of the variance in the perceptual data, all the algorithms we tested make systematic errors on several types of objects. In particular, machine algorithms underestimated distances between symmetric objects compared to human perception. Second, we show that fixing these systematic biases can lead to substantial gains in classification performance. In particular, augmenting a state-of-the-art convolutional neural network with planar/reflection symmetry scores along multiple axes produced significant improvements in classification accuracy (1-10 percent) across categories. These results show that machine vision can be improved by discovering and fixing systematic differences from human vision.

Reverse zoonosis of coronavirus disease-19: Present status and the control by one health approach.

The recent coronavirus disease (COVID-19) outbreak is one of its kind in the history of public health that has created a major global threat. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a zoonotic source and hence, reverse zoonosis (disease transmission from humans to animals) increases the risk and rate of SARS-CoV-2 infection. Serological and molecular analyses and experimental infection studies have identified SARS-CoV-2 infection in several animal species in various countries. Different domestic and wild animals, including cats, dogs, tigers, lions, puma, snow leopard, minks, and pet ferrets, are infected naturally with SARS-CoV-2, mostly through suspected human to animal transmission. In addition, in vivo experimental inoculation studies have reported the susceptibility of cats, ferrets, hamsters, Egyptian fruit bats, and non-human primates to the virus. These experimentally infected species are found to be capable of virus transmission to co-housed animals of the same species. However, SARS-CoV-2 showed poor replication in livestock species such as pigs, chickens, and ducks with no detection of viral RNA after the animals were deliberately inoculated with the virus or exposed to the infected animals. As the pets/companion animals are more susceptible to COVID-19, the infection in animals needs an in-depth and careful study to avoid any future transmissions. The one health approach is the best inter-disciplinary method to understand the consequences of viral spread and prevention in novel host populations for the betterment of public health. Further in this review, we will explain in detail the different natural and experimentally induced cases of human to animal SARS-CoV-2 infection.

Investigation of the Tribological Characteristics of Aluminum 6061-Reinforced Titanium Carbide Metal Matrix Composites.

The current trend in the materials engineering sector is to develop newer materials that can replace the existing materials in various engineering sectors in order to be more and more efficient. Therefore, the present research work is aimed at fabricating and determining the physical, mechanical, and dry sliding wear properties of titanium carbide (TiC)-reinforced aluminum alloy (Al6061) metal matrix composites (MMCs). For the study, the Al6061-TiC microparticle-reinforced composites were fabricated via the liquid metallurgy route through the stir casting method, where the reinforcement of the TiC particles into the Al6061 alloy matrix was added in the range of 0 to 8.0 wt.%, i.e., in the steps of 2.0 wt.%. The synthesis procedure followed the investigation of the various mechanical properties of Al6061-TiC MMCs, such as the density and structure, as well as mechanical and dry wear experimentation. The tests performed on the casted Al6061, as well as its TiC composites, were in harmony with ASTM standards. As per the experimental outcome, it can be confirmed that the increase in the weight percentage of TiC into the Al6061 alloy substantially increases the density, hardness, and tensile strength, at the expense of the percentage of elongation. In addition, the dry wear experiments, performed on a pin-on-disc tribometer, showed that the Al6061-TiC MMCs have superior wear-resistance properties, as compared to those of pure Al6061 alloy. Furthermore, optical micrograph (OM), powdered X-ray diffraction (XRD), energy dispersive spectroscopy (EDS), and scanning electron microscopy (SEM) analyses were employed for the developed Al6061-TiC MMCs before and after the fracture and wear test studies. From the overall analysis of the results, it can be observed that the Al6061-TiC composite material with higher TiC reinforcement displays superior mechanical characteristics.

Factors associated with mortality among moderate and severe patients with COVID-19 in India: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.

Impact of Intraoperative Tumor Spillage in Uterine Leiomyosarcoma: a Retrospective Single-Institution Analysis.

Uterine leiomyosarcoma is a rare female reproductive system tumor which is difficult to distinguish from uterine leiomyoma preoperatively. Manual and power morcellation are used to remove the large uterus through the vagina or small abdominal incision. Worse outcome with use of power morcellation is now clear but impact of manual morcellation on survival outcome not established till date. The objective of the present study was to find impact of tumor spillage and to evaluate influencing factors for oncological outcome and prognosis in uterine leiomyosarcoma patients. This is a single-institutional retrospective cohort study including all uterine leiomyosarcoma patients from January 2005 to December 2017. Role of intraoperative tumor spillage and other influencing factors on oncological outcome were assessed. Thirty-three patients with median follow-up period of 49.7 months were evaluated. Stage 1 and absence of tumor spill had significant association with prolonged progression-free survival. Stage 1 uterine leiomyosarcoma (56.8 vs 6.8 months, p = < 0.001), intraoperative tumor spillage (p = 0.03) and progression-free survival > 15 months (68.5 vs 12.2 months, p = < 0.001) were favourable prognostic factors to predict better survival outcome but unable to establish significance on multivariate analysis. Survival plot did not reach median limit for stage I uterine leiomyosarcoma patients with preoperative suspicion. Age, site of recurrence and mitotic index had no significant association with better survival in the present study. Stage I disease and absence of tumor spillage during surgery improved progression-free survival but did not affect overall survival. Progression-free survival more than 15 months can predict better overall survival.

From Recoding to Peptides for MHC Class I Immune Display: Enriching Viral Expression, Virus Vulnerability and Virus Evasion.

Many viruses, especially RNA viruses, utilize programmed ribosomal frameshifting and/or stop codon readthrough in their expression, and in the decoding of a few a UGA is dynamically redefined to specify selenocysteine. This recoding can effectively increase viral coding capacity and generate a set ratio of products with the same N-terminal domain(s) but different C-terminal domains. Recoding can also be regulatory or generate a product with the non-universal 21st directly encoded amino acid. Selection for translation speed in the expression of many viruses at the expense of fidelity creates host immune defensive opportunities. In contrast to host opportunism, certain viruses, including some persistent viruses, utilize recoding or adventitious frameshifting as part of their strategy to evade an immune response or specific drugs. Several instances of recoding in small intensively studied viruses escaped detection for many years and their identification resolved dilemmas. The fundamental importance of ribosome ratcheting is consistent with the initial strong view of invariant triplet decoding which however did not foresee the possibility of transitory anticodon:codon dissociation. Deep level dynamics and structural understanding of recoding is underway, and a high level structure relevant to the frameshifting required for expression of the SARS CoV-2 genome has just been determined.

Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome.

Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.