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Selenium is an essential antioxidative micronutrient. This study was conducted to characterize the arsenic toxicity induced on the African fig fly, Zaprionus indianus, and its possible amelioration by selenium. We used computational tools and in vivo experiments to elucidate the mechanism of action of arsenic and selenium on Z. indianus larvae. We conducted experiments to study neurobehavioral parameters including learning and memory ability test and crawling and contraction assays. Our in silico study revealed twelve primary targets of arsenic trioxide. The gene ontology annotation of primary and secondary targets of arsenic trioxide revealed selenocysteine metabolic processes as one of the most reliable targets. To validate our in silico data, we analyzed the effect of arsenic trioxide on larvae of Z. indianus and tested the possible amelioration by sodium selenite supplementation. Our data demonstrated that the arsenic trioxide deteriorated the learning and memory ability of 2nd instar larvae of Z. indianus and such effect was reversed by sodium selenite supplementation. Furthermore, crawling and contraction assay done on 3rd instar larvae showed that there was reduction in both parameters upon arsenic trioxide exposure, which was restored with sodium selenite supplementation. Altogether, our computational and in vivo results strongly indicated that the neurobehavioral defects induced by arsenic trioxide on the larvae of Z. indianus can be successfully alleviated in the presence of sodium selenite., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Pavo cristatus population, native to the Indian subcontinent, is thriving well in India. However, the Pavo muticus population, native to the tropical forests of Southeast Asia, has reduced drastically and has been categorised as an endangered group. To understand the probable genetic factors associated with the decline of P. muticus, we compared the mitogenome-encoded proteins (13 proteins) between these two species., Results: Our data revealed that the most frequent variant between these two species was mtND1, which had an alteration in 9.57% residues, followed by mtND5 and mtATP6. We extended our study on the rest of the proteins and observed that cytochrome c oxidase subunits 1, 2, and 3 do not have any change. The 3-dimensional structure of all 13 proteins was modeled using the Phyre2 programme. Our data show that most of the proteins are alpha helical, and the variations observed in P. muticus reside on the surface of the respective proteins. The effect of variation on protein function was also predicted, and our results show that amino acid substitution in mtND1 at 14 sites could be deleterious. Similarly, destabilising changes were observed in mtND1, 2, 3, 4, 5, and 6 and mtATP6-8 due to amino acid substitution in P. muticus. Furthermore, protein disorder scores were considerably altered in mtND1, 2, and 5 of P. muticus., Conclusions: The results presented here strongly suggest that variations in mitogenome-encoded proteins of P. cristatus and P. muticus may alter their structure and functions. Subsequently, these variations could alter energy production and may correlate with the decline in the population of P. muticus., (© 2023. Academy of Scientific Research and Technology.)

Introduction and Objective: Vaccines are administered worldwide to control on-going coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2. Vaccine efficacy is largely contributed by the epitopes present on the viral proteins and their alteration might help emerging variants to escape host immune surveillance. Therefore, this study was designed to study SARS-CoV-2 Nsp13 protein, its epitopes and evolution., Methods: Clustal Omega was used to identify mutations in Nsp13 protein. Secondary structure and disorder score was predicted by CFSSP and PONDR-VSL2 webservers. Protein stability was predicted by DynaMut webserver. B cell epitopes were predicted by IEDB DiscoTope 2.0 tools and their 3D structures were represented by discovery studio. Antigenicity and allergenicity of epitopes were predicted by Vaxijen2.0 and AllergenFPv.1.0. Physiochemical properties of epitopes were predicted by Toxinpred, HLP webserver tool., Results: Our data revealed 182 mutations in Nsp13 among Indian SARS-CoV-2 isolates, which were characterised by secondary structure and per-residue disorderness, stability and dynamicity predictions. To correlate the functional impact of these mutations, we characterised the most prominent B cell and T cell epitopes contributed by Nsp13. Our data revealed twenty-one epitopes, which exhibited antigenicity, stability and interactions with MHC class-I and class-II molecules. Subsequently, the physiochemical properties of these epitopes were analysed. Furthermore, eighteen mutations reside in these Nsp13 epitopes., Conclusions: We report appearance of eighteen mutations in the predicted twenty-one epitopes of Nsp13. Among these, at least seven epitopes closely matches with the functionally validated epitopes. Altogether, our study shows the pattern of evolution of Nsp13 epitopes and their probable implications., Competing Interests: Authors declare no conflict of interest., (© 2023 Elsevier España, S.L.U. All rights reserved.)

Embryonic stem cells (ESCs) are self-renewing and pluripotent. In recent years, factors that control pluripotency, mostly nuclear, have been identified. To identify non-nuclear regulators of ESCs, we screened an endogenously labeled fluorescent fusion-protein library in mouse ESCs. One of the more compelling hits was the cell-cycle-associated protein 1 (CAPRIN1). CAPRIN1 knockout had little effect in ESCs, but it significantly altered differentiation and gene expression programs. Using RIP-seq and SLAM-seq, we found that CAPRIN1 associates with, and promotes the degradation of, thousands of RNA transcripts. CAPRIN1 interactome identified XRN2 as the likely ribonuclease. Upon early ESC differentiation, XRN2 is located in the nucleus and colocalizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner. We propose that CAPRIN1 regulates an RNA degradation pathway operating during early ESC differentiation, thus eliminating undesired spuriously transcribed transcripts in ESCs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several hypotheses have been presented on the origin of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from its identification as the agent causing the current coronavirus disease 19 (COVID-19) pandemic. So far, no solid evidence has been found to support any hypothesis on the origin of this virus, and the issue continue to resurface over and over again. Here we have unfolded a pattern of distribution of several mutations in the SARS-CoV-2 proteins in 24 geo-locations across different continents. The results showed an evenly uneven distribution of the unique protein variants, distinct mutations, unique frequency of common conserved residues, and mutational residues across these 24 geo-locations. Furthermore, ample mutations were identified in the evolutionarily conserved invariant regions in the SARS-CoV-2 proteins across almost all geo-locations studied. This pattern of mutations potentially breaches the law of evolutionary conserved functional units of the beta-coronavirus genus. These mutations may lead to several novel SARS-CoV-2 variants with a high degree of transmissibility and virulence. A thorough investigation on the origin and characteristics of SARS-CoV-2 needs to be conducted in the interest of science and for the preparation of meeting the challenges of potential future pandemics., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest in this work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has relatively short lifespan and is genetically tractable, making it a widely used model organism in aging research. Here, we carried out a systematic and quantitative investigation of yeast aging with single-cell resolution through transcriptomic sequencing. We optimized a single-cell RNA sequencing (scRNA-seq) protocol to quantitatively study the whole transcriptome profiles of single yeast cells at different ages, finding increased cell-to-cell transcriptional variability during aging. The single-cell transcriptome analysis also highlighted key biological processes or cellular components, including oxidation-reduction process, oxidative stress response (OSR), translation, ribosome biogenesis and mitochondrion that underlie aging in yeast. We uncovered a molecular marker of FIT3, indicating the early heterogeneity during aging in yeast. We also analyzed the regulation of transcription factors and further characterized the distinctive temporal regulation of the OSR by YAP1 and proteasome activity by RPN4 during aging in yeast. Overall, our data profoundly reveal early heterogeneity during aging in yeast and shed light on the aging dynamics at the single cell level., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Open reading frame 8 (ORF8) shows one of the highest levels of variability among accessory proteins in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits the presentation of viral antigens by the major histocompatibility complex class I (MHC-I), which interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 in evading immunity and plays a role in SARS-CoV-2 replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein, defines the B.1.1.7 lineage of SARS-CoV-2, engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) with the Q27STOP mutations were identified among 49,055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents, which include Africa, Asia, Europe and South America. Based on various quantitative features, such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, nine possible T-ORF8 unique variants were defined. The question as to whether T-ORF8 variants function similarly to the wild type ORF8 is yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures., Competing Interests: Vasco Azevedo, Debmalya Barh and Vladimir N Uversky are Academic Editors for PeerJ. Kenneth Lundstrom is employed by PanTherapeutics., (© 2022 Hassan et al.)

The coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- CoV-2) with an estimated fatality rate of less than 1%. The SARS-CoV-2 accessory proteins ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10 possess putative functions to manipulate host immune mechanisms. These involve interferons, which appear as a consensus function, immune signaling receptor NLRP3 (NLR family pyrin domain-containing 3) inflammasome, and inflammatory cytokines such as interleukin 1β (IL-1β) and are critical in COVID-19 pathology. Outspread variations of each of the six accessory proteins were observed across six continents of all complete SARS-CoV-2 proteomes based on the data reported before November 2020. A decreasing order of percentage of unique variations in the accessory proteins was determined as ORF3a > ORF8 > ORF7a > ORF6 > ORF10 > ORF7b across all continents. The highest and lowest unique variations of ORF3a were observed in South America and Oceania, respectively. These findings suggest that the wide variations in accessory proteins seem to affect the pathogenicity of SARS-CoV-2., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Various lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have contributed to prolongation of the Coronavirus Disease 2019 (COVID-19) pandemic. Several non-synonymous mutations in SARS-CoV-2 proteins have generated multiple SARS-CoV-2 variants. In our previous report, we have shown that an evenly uneven distribution of unique protein variants of SARS-CoV-2 is geo-location or demography-specific. However, the correlation between the demographic transmutability of the SARS-CoV-2 infection and mutations in various proteins remains unknown due to hidden symmetry/asymmetry in the occurrence of mutations. This study tracked how these mutations are emerging in SARS-CoV-2 proteins in six model countries and globally. In a geo-location, considering the mutations having a frequency of detection of at least 500 in each SARS-CoV-2 protein, we studied the country-wise percentage of invariant residues. Our data revealed that since October 2020, highly frequent mutations in SARS-CoV-2 have been observed mostly in the Open Reading Frame (ORF) 7b and ORF8, worldwide. No such highly frequent mutations in any of the SARS-CoV-2 proteins were found in the UK, India, and Brazil, which does not correlate with the degree of transmissibility of the virus in India and Brazil. However, we have found a signature that SARS-CoV-2 proteins were evolving at a higher rate, and considering global data, mutations are detected in the majority of the available amino acid locations. Fractal analysis of each protein's normalized factor time series showed a periodically aperiodic emergence of dominant variants for SARS-CoV-2 protein mutations across different countries. It was noticed that certain high-frequency variants have emerged in the last couple of months, and thus the emerging SARS-CoV-2 strains are expected to contain prevalent mutations in the ORF3a, membrane, and ORF8 proteins. In contrast to other beta-coronaviruses, SARS-CoV-2 variants have rapidly emerged based on demographically dependent mutations. Characterization of the periodically aperiodic nature of the demographic spread of SARS-CoV-2 variants in various countries can contribute to the identification of the origin of SARS-CoV-2., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The RNA dependent RNA polymerase (RdRp) plays crucial role in virus life cycle by replicating the viral genome. The SARS-CoV-2 is an RNA virus that rapidly spread worldwide and acquired mutations. This study was carried out to identify mutations in RdRp as the SARS-CoV-2 spread in India. We compared 50217 RdRp sequences reported from India with the first reported RdRp sequence from Wuhan, China to identify 223 mutations acquired among Indian isolates. Our protein modelling study revealed that several mutants can potentially alter stability and flexibility of RdRp. We predicted the potential B cell epitopes contributed by RdRp and identified thirty-six linear continuous and twenty-five discontinuous epitopes. Among 223 RdRp mutants, 44% of them localises in the B cell epitopes region. Altogether, this study highlights the need to identify and characterize the variations in RdRp to understand the impact of these mutations on SARS-CoV-2., (Copyright © 2021 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

The SARS-CoV-2 is rapidly evolving and new mutations are being reported from different parts of the world. In this study, we investigated the variations occurring in the nucleocapsid phosphoprotein (N-protein) of SARS-CoV-2 from India. We used several in silico prediction tools to characterise N-protein including IEDB webserver for B cell epitope prediction, Vaxijen 2.0 and AllergenFP v.1.0 for antigenicity and allergenicity prediction of epitopes, CLUSTAL Omega for mutation identification and PONDR webserver for disorder prediction, PROVEAN score for protein function and iMutantsuite for protein stability prediction. Our results show that 81 mutations have occurred in this protein among Indian SARS-CoV-2 isolates. Subsequently, we characterized the N-protein epitopes to identify seven most promising peptides. We mapped these mutations with seven N-protein epitopes to identify the loss of antigenicity in two of them, suggesting that the mutations occurring in the SARS-CoV-2 genome contribute to the alteration in the properties of epitopes. Altogether, our data strongly indicates that N-protein is gaining several mutations in its B cell epitope regions that might alter protein function., Competing Interests: CONFLICT OF INTERESTThe authors declare that they have no conflicts of interest., (© Allerton Press, Inc. 2022, ISSN 0096-3925, Moscow University Biological Sciences Bulletin, 2022, Vol. 77, No. 4, pp. 251–257. © Allerton Press, Inc., 2022.Russian Text © The Author(s), 2022, published in Vestnik Moskovskogo Universiteta, Seriya 16: Biologiya, 2022, Vol. 77, No. 00000, pp. 00000–00000.)

The devastating impact of the ongoing coronavirus disease 2019 (COVID-19) on public health, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has made targeting the COVID-19 pandemic a top priority in medical research and pharmaceutical development. Surveillance of SARS-CoV-2 mutations is essential for the comprehension of SARS-CoV-2 variant diversity and their impact on virulence and pathogenicity. The SARS-CoV-2 open reading frame 10 (ORF10) protein interacts with multiple human proteins CUL2, ELOB, ELOC, MAP7D1, PPT1, RBX1, THTPA, TIMM8B, and ZYG11B expressed in lung tissue. Mutations and co-occurring mutations in the emerging SARS-CoV-2 ORF10 variants are expected to impact the severity of the virus and its associated consequences. In this article, we highlight 128 single mutations and 35 co-occurring mutations in the unique SARS-CoV-2 ORF10 variants. The possible predicted effects of these mutations and co-occurring mutations on the secondary structure of ORF10 variants and host protein interactomes are presented. The findings highlight the possible effects of mutations and co-occurring mutations on the emerging 140 ORF10 unique variants from secondary structure and intrinsic protein disorder perspectives., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The spike (S) protein is a critical determinant of the infectivity and antigenicity of SARS-CoV-2. Several mutations in the S protein of SARS-CoV-2 have already been detected, and their effect in immune system evasion and enhanced transmission as a cause of increased morbidity and mortality are being investigated. From pathogenic and epidemiological perspectives, S proteins are of prime interest to researchers. This study focused on the unique variants of S proteins from six continents: Asia, Africa, Europe, Oceania, South America, and North America. In comparison to the other five continents, Africa had the highest percentage of unique S proteins (29.1%). The phylogenetic relationship implies that unique S proteins from North America are significantly different from those of the other five continents. They are most likely to spread to the other geographic locations through international travel or naturally by emerging mutations. It is suggested that restriction of international travel should be considered, and massive vaccination as an utmost measure to combat the spread of the COVID-19 pandemic. It is also further suggested that the efficacy of existing vaccines and future vaccine development must be reviewed with careful scrutiny, and if needed, further re-engineered based on requirements dictated by new emerging S protein variants., (Copyright © 2018. Published by Elsevier B.V.)

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19) that exhibits an overwhelming contagious capacity over other human coronaviruses (HCoVs). This structural snapshot describes the structural bases underlying the pandemic capacity of SARS-CoV-2 and explains its fast motion over respiratory epithelia that allow its rapid cellular entry. Based on notable viral spike (S) protein features, we propose that the flat sialic acid-binding domain at the N-terminal domain (NTD) of the S1 subunit leads to more effective first contact and interaction with the sialic acid layer over the epithelium, and this, in turn, allows faster viral 'surfing' of the epithelium and receptor scanning by SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE-2) protein on the epithelial surface is the primary entry receptor for SARS-CoV-2, and protein-protein interaction assays demonstrate high-affinity binding of the spike protein (S protein) to ACE-2. To date, no high-frequency mutations were detected at the C-terminal domain of the S1 subunit in the S protein, where the receptor-binding domain (RBD) is located. Tight binding to ACE-2 by a conserved viral RBD suggests the ACE2-RBD interaction is likely optimal. Moreover, the viral S subunit contains a cleavage site for furin and other proteases, which accelerates cell entry by SARS-CoV-2. The model proposed here describes a structural basis for the accelerated host cell entry by SARS-CoV-2 relative to other HCoVs and also discusses emerging hypotheses that are likely to contribute to the development of antiviral strategies to combat the pandemic capacity of SARS-CoV-2., (© 2020 Federation of European Biochemical Societies.)

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.

The current Coronavirus Disease 19 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) shows similar pathology to MERS and SARS-CoV, with a current estimated fatality rate of 1.4%. Open reading frame 10 (ORF10) is a unique SARS-CoV-2 accessory protein, which contains eleven cytotoxic T lymphocyte (CTL) epitopes each of nine amino acids in length. Twenty-two unique SARS-CoV-2 ORF10 variants have been identified based on missense mutations found in sequence databases. Some of these mutations are predicted to decrease the stability of ORF10 in silico physicochemical and structural comparative analyses were carried out on SARS-CoV-2 and Pangolin-CoV ORF10 proteins, which share 97.37% amino acid (aa) homology. Though there is a high degree of ORF10 protein similarity of SARS-CoV-2 and Pangolin-CoV, there are differences of these two ORF10 proteins related to their sub-structure (loop/coil region), solubility, antigenicity and shift from strand to coil at aa position 26 (tyrosine). SARS-CoV-2 ORF10, which is apparently expressed in vivo since reactive T cell clones are found in convalescent patients should be monitored for changes which could correlate with the pathogenesis of COVID-19., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immune evasion is one of the unique characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attributed to its ORF8 protein. This protein modulates the adaptive host immunity through down-regulation of MHC-1 (Major Histocompatibility Complex) molecules and innate immune responses by surpassing the host's interferon-mediated antiviral response. To understand the host's immune perspective in reference to the ORF8 protein, a comprehensive study of the ORF8 protein and mutations possessed by it have been performed. Chemical and structural properties of ORF8 proteins from different hosts, such as human, bat, and pangolin, suggest that the ORF8 of SARS-CoV-2 is much closer to ORF8 of Bat RaTG13-CoV than to that of Pangolin-CoV. Eighty-seven mutations across unique variants of ORF8 in SARS-CoV-2 can be grouped into four classes based on their predicted effects (Hussain et al., 2021) [1]. Based on the geo-locations and timescale of sample collection, a possible flow of mutations was built. Furthermore, conclusive flows of amalgamation of mutations were found upon sequence similarity analyses and consideration of the amino acid conservation phylogenies. Therefore, this study seeks to highlight the uniqueness of the rapidly evolving SARS-CoV-2 through the ORF8., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The population of catfish, Clarias batrachus has substantially diminished in various countries and studies show that another related species Clarias gariepinus is replacing it. The better adaptability and survivability of C. gariepinus over C. batrachus could be attributed to the metabolic differences between these two species, which is primarily regulated by mitochondrial activities. To understand the reasons behind this phenomenon, we performed in silico analyses to decipher the differences between the proteins encoded by the mitochondrial genome of these two related species. Our analysis revealed that out of thirteen, twelve proteins encoded by the mitochondrial genome of these two species have substantial variations between them. We characterised these variations by analysing their effect on secondary structure, intrinsic disorder predisposition, and functional impact on protein and stability parameters. Our data show that most of the parameters are changing between these two closely related species. Altogether, we demonstrate the molecular insights into the mitochondrial genome-encoded proteins of these two species and predict their effect on protein function and stability that might be helping C. gariepinus to gain survivability better than the C. batrachus ., Competing Interests: Authors declare no conflict of interests., (© 2021 The Authors.)

Coronavirus disease- 2019 (COVID-19) has rapidly become a major threat to humans due to its high infection rate and deaths caused worldwide. This disease is caused by an RNA virus, Severe Acquired Respiratory Syndrome -Corona Virus-2 (SARS-CoV-2). This class of viruses have a high rate of mutation than DNA viruses that enables them to adapt and also evade host immune system. Here, we compared the first known Nucleocapsid Phosphoprotein (N protein) sequence of SARS-CoV-2 from China with the sequences from Indian COVID-19 patients to understand, if this virus is also mutating, as it is spreading to new locations. Our data revealed twenty mutations present among Indian isolates. Out of these, mutation at six positions led to changes in the secondary structure of N protein. Further, we also show that these mutations are primarily destabilising the protein structure. The candidate mutations identified in this study may help to speed up the understanding of variations occurring in SARS-CoV-2., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Severe acquired respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread worldwide and acquired multiple mutations in its genome. Orf3a, an accessory protein encoded by the genome of SARS-CoV-2, plays a significant role in viral infection and pathogenesis. In the present in-silico study, 15,928 sequences of Orf3a reported worldwide were compared to identify variations in this protein. Our analysis revealed the occurrence of mutations at 173 residues of Orf3a protein. Subsequently, protein modelling was performed that revealed twelve mutations which can considerably affect the stability of Orf3a. Among the 12 mutations, three mutations (Y160H, D210Y and S171L) also lead to alterations in secondary structure and protein disorder parameters of the Orf3a protein. Further, we used predictive tools to identify five promising epitopes of B-cells, which resides in the mutated regions of Orf3a. Altogether, our study sheds light on the variations occurring in Orf3a that might contribute to alteration in protein structure and function., Competing Interests: Authors declare no conflict of interests., (© 2021 Published by Elsevier B.V.)

SARS-CoV-2 genome encodes four structural proteins that include the spike glycoprotein, membrane protein, envelope protein and nucleocapsid phosphoprotein (N-protein). The N-protein interacts with viral genomic RNA and helps in packaging. As SARS-CoV-2 spread to almost all countries worldwide within 2-3 months, it also acquired mutations in its RNA genome. Therefore, this study was conducted with an aim to identify the variations present in N-protein of SARS-CoV-2. Here, we analysed 4,163 reported sequence of N-protein from United States of America (USA) and compared them with the first reported sequence from Wuhan, China. Our study identified 107 mutations that reside all over the N-protein. Further, we show the high rate of mutations in intrinsically disordered regions (IDRs) of N-protein. Our study show 45% residues of IDR2 harbour mutations. The RNA-binding domain (RBD) and dimerization domain of N-protein also have mutations at key residues. We further measured the effect of these mutations on N-protein stability and dynamicity and our data reveals that multiple mutations can cause considerable alterations. Altogether, our data strongly suggests that N-protein is one of the mutational hotspot proteins of SARS-CoV-2 that is changing rapidly and these mutations can potentially interferes with various aspects of N-protein functions including its interaction with RNA, oligomerization and signalling events., Competing Interests: The author declares that they have no competing interests., (© 2021 Azad.)

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

A recent outburst of the pandemic caused by a member of the coronaviridae family identified as SARS-CoV-2. The highly contagious nature of the virus allows it to spread rapidly worldwide and caused severe healthcare and economic distress. So far, no proper line of treatment or vaccines has been available against SARS-CoV-2. Since, the infected people rapidly increased, causing the saturation of healthcare systems with coronavirus disease (COVID-19) patients. As the virus spread to new locations it also acquired various mutations. Here, in this study, we focused on identifying mutations in one of the crucial complex of SARS-CoV-2, the Nsp10-Nsp16 2'- O -methyltransferase complex. This complex plays indispensable role in the post-transcriptional modifications of viral RNA by its capping. We analysed 208 sequences of Nsp10-Nsp16 reported from India and compared with first reported sequence from Wuhan, China. Our analysis revealed a single mutation in Nsp10 and five mutations in Nsp16 protein. We also show that these mutations are leading to alteration in the secondary structure of Nsp10-Nsp16. Further, the protein modelling studies revealed that the mutation of both Nsp10-Nsp16 impacts the protein dynamicity and stability. Altogether, this study provides novel insights into the variations observed in the proteins of SARS-CoV-2 that might have functional consequences., Competing Interests: Authors declare no conflict of interests., (© 2020 The Author.)

SARS-CoV-2, the causative agent of the COVID-19 pandemic, is an RNA virus that has inherent high rate of mutation. Due to the mutations, the virus evolves at a rapid pace that helps them to survive better inside the host. One of the hotspots of pharmacological interventions is to inhibit binding of virus with the host cells, which is mediated by Spike glycoprotein of SARS-CoV-2 and ACE2 receptors present on the human cells. This study was conducted with an aim to identify and characterise the mutation (s) present in the Spike glycoprotein of the SARS-CoV-2. Towards this, an in silico methodology was used, and the mutations on Spike glycoprotein were identified by comparing the Spike glycoprotein of first reported sequence from Wuhan wet seafood market virus with the available sequences of SARS-CoV-2 from Indian isolates. Our analysis revealed the presence of twenty-five mutations in Spike glycoprotein among Indian SARS-CoV-2 isolates. These mutations spread all over the protein and can be clustered at least into four distinct positions. Further, mutations at eleven positions exhibited alterations in the secondary structure of the polypeptide chain. We also investigated the influence of these mutations on overall protein dynamics and have shown that they affect the dynamic stability of the Spike glycoprotein., Competing Interests: Authors declare no conflict of interests., (© 2020 Elsevier Inc. All rights reserved.)

Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.

The rapid development of the SARS-CoV-2 mediated COVID-19 pandemic has been the cause of significant health concern, highlighting the immediate need for effective antivirals. SARS-CoV-2 is an RNA virus that has an inherently high mutation rate. These mutations drive viral evolution and genome variability, thereby facilitating viruses to have rapid antigenic shifting to evade host immunity and to develop drug resistance. Viral RNA-dependent RNA polymerases (RdRp) perform viral genome duplication and RNA synthesis. Therefore, we compared the available RdRp sequences of SARS-CoV-2 from Indian isolates and the 'Wuhan wet sea food market virus' sequence to identify, if any, variation between them. Our data revealed the occurrence of seven mutations in Indian isolates of SARS-CoV-2. The secondary structure prediction analysis of these seven mutations shows that three of them cause alteration in the structure of RdRp. Furthermore, we did protein modelling studies to show that these mutations can potentially alter the stability of the RdRp protein. Therefore, we propose that RdRp mutations in Indian SARS-CoV-2 isolates might have functional consequences that can interfere with RdRp targeting pharmacological agents., Competing Interests: The authors declare that they have no competing interests., (© 2020 Chand et al.)

Background: Alzheimer's disease (AD) is a chronic condition that progresses over time. While several therapeutic approaches have been developed, none have substantially altered disease progression. One explanation is that the disease is multi factorial., Objective: Using the Affirmativ Health Personal Therapeutic Program (PTPr), we sought to determine whether a comprehensive and personalized program could improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early stage AD., Methods: 35 individuals submitted blood samples and Montreal Cognitive Assessment (MoCA) scores, and answered intake questions. Individuals and caregivers participated in a four-day immersion program, which included Personal Therapeutic Plans (PTP), consultations with clinical practitioners, and explanations of the PTPr and PTP. Participants had follow-up by telemonitoring, with repeat blood sample analysis, updates regarding lifestyle choices, current medications and supplements, and MoCA testing at least once between 3 and 12 months after the PTPr., Results: By comparing baseline to follow-up testing, we determined several risk factor scores, including blood glucose and insulin levels, and levels of vitamins B12, D3, and E, improved either in the entire participant pool or specifically in individuals with measures outside the normal range for specific factors. MoCA scores were stabilized in the entire participant pool and significantly improved in individuals scoring 24 or less at baseline., Conclusion: Our findings provide evidence that a comprehensive and personalized approach designed to mitigate AD risk factors can improve risk factor scores and stabilize cognitive function, warranting more extensive and placebo-controlled clinical studies., Competing Interests: G.S., A.M., D.M.K., and B.K.K. are all affiliated with Affirmativ Health, for which D.M.K. also maintains an equity position., (© 2020 – IOS Press and the authors. All rights reserved.)

Purpose: To establish whether first-order statistical features from [ 18 F]fluoride and 2-deoxy-2-[ 18 F] fluoro-D-glucose ([ 18 F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) demonstrate incremental value in skeletal metastasis response assessment compared with maximum standardised uptake value (SUV max )., Procedures: Sixteen patients starting endocrine treatment for de novo or progressive breast cancer bone metastases were prospectively recruited to undergo [ 18 F]fluoride and [ 18 F]FDG PET/CT scans before and 8 weeks after treatment. Percentage changes in SUV parameters, metabolic tumour volume (MTV), total lesion metabolism (TLM), standard deviation (SD), entropy, uniformity and absolute changes in kurtosis and skewness, from the same ≤ 5 index lesions, were measured. Clinical response to 24 weeks, assessed by two experienced oncologists blinded to PET/CT imaging findings, was used as a reference standard and associations were made between parameters and progression free and overall survival., Results: [ 18 F]fluoride PET/CT: In four patients (20 lesions) with progressive disease (PD), TLM and kurtosis predicted PD better than SUV max on a patient basis (4, 4 and 3 out of 4, respectively) and TLM, entropy, uniformity and skewness on a lesion basis (18, 16, 16, 18 and 15 out of 20, respectively). Kurtosis was independently associated with PFS (p = 0.033) and OS (p = 0.008) on Kaplan-Meier analysis. [ 18 F]FDG PET: No parameter provided incremental value over SUV max in predicting PD or non-PD. TLM was significantly associated with OS (p = 0.041) and skewness with PFS (p = 0.005). Interlesional heterogeneity of response was seen in 11/16 and 8/16 patients on [ 18 F]fluoride and [ 18 F]FDG PET/CT, respectively., Conclusion: With [ 18 F]fluoride PET/CT, some first-order features, including those that take into account lesion volume but also some heterogeneity parameters, provide incremental value over SUV max in predicting clinical response and survival in breast cancer patients with bone metastases treated with endocrine therapy. With [ 18 F]FDG PET/CT, no first-order parameters were more accurate than SUV max although TLM and skewness were associated with OS and PFS, respectively. Intra-patient heterogeneity of response occurs commonly between metastases with both tracers and most parameters.

Purpose: To compare [ 18 F]-fluorodeoxyglucose (FDG) and [ 18 F]-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) with whole-body magnetic resonance with diffusion-weighted imaging (WB-MRI), for endocrine therapy response prediction at 8 weeks in bone-predominant metastatic breast cancer., Patients and Methods: Thirty-one patients scheduled for endocrine therapy had up to five bone metastases measured [FDG, NaF PET/CT: maximum standardized uptake value (SUV max ); WB-MRI: median apparent diffusion coefficient (ADC med )] at baseline and 8 weeks. To detect the flare phenomenon, a 12-week NaF PET/CT was also performed if 8-week SUV max increased. A 25% parameter change differentiated imaging progressive disease (PD) from non-PD and was compared to a 24-week clinical reference standard and progression-free survival (PFS)., Results: Twenty-two patients (median age, 58.6 years, range, 40-79 years) completing baseline and 8-week imaging were included in the final analysis. Per-patient % change in NaF SUV max predicted 24-week clinical PD with sensitivity, specificity and accuracy of 60, 73.3, and 70%, respectively. For FDG SUV max the results were 0, 100, and 76.2% and for ADC med , 0, 100 and 72.2%, respectively. PFS < 24 weeks was associated with % change in SUV max (NaF: 41.7 vs. 0.7%, p = 0.039; FDG: - 4.8 vs. - 28.6%, p = 0.005) but not ADC med (- 0.5 vs. 10.1%, p = 0.098). Interlesional response heterogeneity occurred in all modalities and NaF flare occurred in seven patients., Conclusions: FDG PET/CT and WB-MRI best predicted clinical non-PD and both FDG and NaF PET/CT predicted PFS < 24 weeks. Lesional response heterogeneity occurs with all modalities and flare is common with NaF PET/CT.

Our purpose was to establish whether noninvasive measurement of changes in 18 F-fluoride metabolic flux to bone mineral (K i ) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUV max and SUV mean Methods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18 F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18 F-fluoride activity concentrations, and K i in individual bone metastases was calculated using a previously validated method. Percentage changes in K i , SUV max , and SUV mean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean K i significantly increased (>25%) in all, SUV max in 3, and SUV mean in 2. Of the 8 non-PD patients, K i decreased or remained stable in 7, SUV max in 5, and SUV mean in 6. A significant mean percentage increase from baseline for K i , compared with SUV max and SUV mean , occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, K i more reliably differentiated PD from non-PD than did SUV max and SUV mean , probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Post-translational modifications (PTMs) of histone proteins play a crucial role in the regulation of chromatin structure and functions. Studies in the last few decades have revealed the significance of histone PTMs in key cellular processes including DNA replication, repair, transcription, apoptosis and cell cycle regulation. The PTMs on histones are carried out by chromatin modifiers, which are reversible in nature. The dynamic activity of chromatin modifiers maintains the levels of different PTMs on histones. The modified histones are recognized by reader proteins, which recruit effector proteins to regulate the function. The interplay between histone PTMs and chromatin dynamics plays a major role in the regulation of most of the cellular processes. Importantly, the perturbations in the histone PTMs by various intrinsic or extrinsic factors can cause defects in fundamental cellular processes leading to a wide range of diseases. The proteolytic clipping of histone proteins has also been shown to regulate many biological processes. Histone clipping has been observed from yeast to mammals, suggesting that this mechanism is a conserved epigenetic phenomenon. In this review, we have summarized the significance of histone clipping and provided future directions to comprehend the mechanism of this distinct and poorly understood epigenetic event., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of 99m Tc-maraciclatide, a radiopharmaceutical targeting α v β 3 integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy., Methods: The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with 99m Tc-maraciclatide before (n = 17) and 12 weeks after (n = 11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria., Results: Before treatment, metastases showed specific 99m Tc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389-740 HU) showed lower T:M ratios (4.22 vs. 7.04, p = 0.02) than less sclerotic/lytic lesions (46-381 HU). Patients with progressive disease (PD; n = 5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and -8.0%, p = 1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (-21.9, and -27.2%, p = 0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r = -0.59, p = 0.006)., Conclusions: 99m Tc-maraciclatide accumulates in PCa bone metastases in keeping with increased α v β 3 integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and 99m Tc-maraciclatide imaging may be a potential method for assessing early response.

Neuronal stimulation leads to immediate early gene (IEG) expression through calcium-dependent mechanisms. In recent years, considerable attention has been devoted to the transcriptional responses after neuronal stimulation, but relatively little is known about the changes in chromatin dynamics that follow neuronal activation. Here, we use fluorescence recovery after photobleaching, biochemical fractionations, and chromatin immunoprecipitation to show that KCl-induced depolarization in primary cultured cortical neurons causes a rapid release of the linker histone H1 from chromatin, concomitant with IEG expression. H1 release is repressed by PARP inhibition, PARP1 deletion, a non-PARylatable H1, as well as phosphorylation inhibitions and a nonphosphorylatable H1, leading to hindered IEG expression. Further, H1 is replaced by PARP1 on IEG promoters after neuronal stimulation, and PARP inhibition blocks this reciprocal binding response. Our results demonstrate the relationship between neuronal excitation and chromatin plasticity by identifying the roles of polyadenosine diphosphate ribosylation and phosphorylation of H1 in regulating H1 chromatin eviction and IEG expression in stimulated neurons., (© 2018 Azad et al.)

Embryonic stem cells (ESCs), with their dual capacity to self-renew and differentiate, are commonly used to study differentiation, epigenetic regulation, lineage choices, and more. Using non-directed retroviral integration of a YFP/Cherry exon into mouse ESCs, we generated a library of over 200 endogenously tagged fluorescent fusion proteins and present several proof-of-concept applications of this library. We show the utility of this library to track proteins in living cells; screen for pluripotency-related factors; identify heterogeneously expressing proteins; measure the dynamics of endogenously labeled proteins; track proteins recruited to sites of DNA damage; pull down tagged fluorescent fusion proteins using anti-Cherry antibodies; and test for interaction partners. Thus, this library can be used in a variety of different directions, either exploiting the fluorescent tag for imaging-based techniques or utilizing the fluorescent fusion protein for biochemical pull-down assays, including immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, and more., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Embryonic stem cells (ESCs) are regulated by pluripotency-related transcription factors in concert with chromatin regulators. To identify additional stem cell regulators, we screened a library of endogenously labeled fluorescent fusion proteins in mouse ESCs for fluorescence loss during differentiation. We identified SET, which displayed a rapid isoform shift during early differentiation from the predominant isoform in ESCs, SETα, to the primary isoform in differentiated cells, SETβ, through alternative promoters. SETα is selectively bound and regulated by pluripotency factors. SET depletion causes proliferation slowdown and perturbed neuronal differentiation in vitro and developmental arrest in vivo, and photobleaching methods demonstrate SET's role in maintaining a dynamic chromatin state in ESCs. This work identifies an important regulator of pluripotency and early differentiation, which is controlled by alternative promoter usage., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Histone proteins are subjected to a wide array of reversible and irreversible post-translational modifications (PTMs) (Bannister and Kouzarides, 2011; Azad and Tomar, 2014). The PTMs on histones are known to regulate chromatin structure and function. Histones are irreversibly modified by proteolytic clipping of their tail domains. The proteolytic clipping of histone tails is continuously attracting interest of researchers in the field of chromatin biology. We can recapitulate H3-clipping by performing in vitro H3 cleavage assay. Here, we are presenting the detailed protocol to perform in vitro H3 cleavage assay., (Copyright © 2017 The Authors; exclusive licensee Bio-protocol LLC.)

Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin., (© 2016 Federation of European Biochemical Societies.)

In oncology, the skeleton is one of the most frequently encountered sites for metastatic disease and thus early detection not only has an impact on an individual patient's management but also on the overall outcome. Multiparametric and multimodal hybrid PET/computed tomography and PET/MR imaging have revolutionized imaging for bone metastases, but irrespective of tumor biology or morphology of the bone lesion it remains unclear which imaging modality is the most clinically relevant to guide individualized cancer care. In this review, we highlight the current clinical challenges of PET imaging in evaluation and quantification of skeletal tumor burden and its impact on personalized cancer management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is growing evidence that molecular imaging of bone metastases with positron-emission tomography (PET) can improve diagnosis and treatment response assessment over current conventional standard imaging methods, although cost-effectiveness has not been assessed. In most cancer types, 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG)-PET is an accurate method for detecting bone metastases. For example, in breast cancer, combined (18)F-FDG-PET and computed tomography (CT) is more sensitive at detecting bone metastases than (99m)technetium (Tc)-labelled diphosphonate planar bone scintigraphy (BS) and there is increasing evidence to support the use of serial (18)F-FDG-PET for the assessment of osseous response to treatment. Preliminary data suggest improved diagnostic accuracy of (18)F-FDG-PET-CT in a number of other malignancies including lung, thyroid, head and neck, gastro-oesophageal cancers, and osteosarcoma. As a bone-specific tracer, there is accumulating evidence to support the use of sodium (18)F-fluoride ((18)F-NaF) PET-CT in the diagnosis of skeletal metastases in breast and prostate cancer, although relatively little data are available to support its use for assessment of treatment response. In prostate cancer, (11)C-choline and (18)F-choline PET-CT have better specificities than (18)F-NaF-PET-CT, but equivalent sensitivities in the detection of bone metastases. We review the current literature for staging and response assessment of bone metastases in different cancers., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Transcription is a fundamental process that is tightly regulated by transcription factors to maintain cellular homeostasis. Transcription factors have DNA-binding domains, some of which are sequence specific, and are found throughout the eukaryotic kingdom. Recent studies have revealed the molecular mechanisms by which transcription factors perform their functions. In the budding yeast Saccharomyces cerevisiae, Rap1 (ScRap1) can either activate or repress transcription. This bimodal transcriptional activity has led to the widespread study of the mode of action of ScRap1. This review summarizes current knowledge about yeast ScRap1, including its structure, mechanisms of transcription regulation, and biological functions, and the future directions in the field.

The proteolytic clipping of histone tails has recently emerged as a novel form of irreversible post-translational modification (PTM) of histones. Histone clipping has been implicated as a regulatory process leading to the permanent removal of PTMs from histone proteins. However, there is scarcity of literature that describes the identification and characterization of histone-specific proteases. Here, we employed various biochemical methods to report histone H3-specific proteolytic activity from budding yeast. Our results demonstrate that H3 proteolytic activity was associated with sepharose bead matrices and activity was not affected by a variety of stress conditions. We have also identified the existence of an unknown protein that acts as a physiological inhibitor of the H3-clipping activity of yeast H3 protease. Moreover, through protease inhibition assays, we have also characterized yeast H3 protease as a serine protease. Interestingly, unlike glutamate dehydrogenase (GDH), yeast H3 proteolytic activity was not inhibited by Stefin B. Together, our findings suggest the existence of a novel H3 protease in yeast that is different from other reported histone H3 proteases. The presence of histone H3 proteolytic activity, along with the physiological inhibitor in yeast, suggests an interesting molecular mechanism that regulates the activity of histone proteases. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Bone metastases are common in patients with advanced breast cancer. Given the significant associated morbidity, the introduction of new, effective systemic therapies, and the improvement in survival time, early detection and response assessment of skeletal metastases have become even more important. Although planar bone scanning has recognized limitations, in particular, poor specificity in staging and response assessment, it continues to be the main method in current clinical practice for staging of the skeleton in patients at risk of bone metastases. However, the accuracy of bone scanning can be improved with the addition of SPECT/CT. There have been reported improvements in sensitivity and specificity for staging of the skeleton with either bone-specific PET/CT tracers, such as (18)F-NaF, or tumor-specific tracers, such as (18)F-FDG, although these methods are less widely available and more costly. There is a paucity of data on the use of (18)F-NaF PET/CT for response assessment in breast cancer, but there is increasing evidence that (18)F-FDG PET/CT may improve on current methods in this regard. At the same time, interest and experience in using whole-body morphologic MRI augmented with diffusion-weighted imaging for both staging and response assessment in the skeleton have been increasing. However, data on comparisons of these methods with PET methods to determine the best technique for current clinical practice or for clinical trials are insufficient. There are early data supporting the use (18)F-FDG PET/MRI to assess malignant disease in the skeleton, with the possibility of taking advantage of the synergies offered by combining morphologic, physiologic, and metabolic imaging., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Our ability to accurately assess the skeleton for metastases in breast and prostate cancers has improved significantly in recent years with hybrid imaging methods. Nevertheless, no consensus has been reached on the best imaging modality for diagnosis and treatment response assessment of skeletal disease. Hybrid SPECT/CT has low false-positive and false-negative rates compared with planar bone scintigraphy (BS) or BS augmented with SPECT in breast and prostate cancers. In breast cancer, 18F-FDG PET is more sensitive and accurate at detecting bone metastases than BS. Currently, little evidence has accrued to support the superiority of 18F-fluoride (18F-NaF) PET in diagnosing osseous metastases or monitoring treatment response in breast cancer when compared with conventional imaging. In prostate cancer, the sensitivities of 18F-NaF PET/CT, 18F-fluorocholine (18F-choline), or 11C-choline PET/CT are equivalent, although 11C-/18F-choline PET/CT scans are more specific. Whole-body MRI, using anatomical sequences complemented by diffusion-weighted MRI, shows early evidence of utility for diagnosis and monitoring therapy response. We review the literature for staging and response assessment in metastatic breast and prostate cancer. While staging accuracy has significantly improved with hybrid imaging, optimal methods for assessing early treatment response have not been determined, and this is an area of active research.

The Nrd1-Nab3-Sen1 (NNS) complex terminates transcription of non-coding RNA genes and mediates degradation of the produced transcript by the nuclear exosome. The NNS complex also represses some stress response genes, by stimulating premature termination. A well-characterized stress response in yeast is flocculation, where cells aggregate to form flocs under expression of lectin-encoding genes designated as FLOs. In this study, we demonstrated the role of the NNS complex and Rrp6p in the expression of flocculation genes: FLO1, FLO5, FLO9, and FLO10. Furthermore, a deletion mutant of the RNA processing machinery (RNT1), and SEN1 mutants that are unable to interact with Rnt1p, exhibit a flocculation phenotype. In summary, we have identified a cooperative role of Rnt1p, Rrp6p and the NNS complex in the repression of FLO genes., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)