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Allen, M. D., Bycroft, M., & Zinzalla, G. (2020). Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein-protein interactions. Protein science : a publication of the Protein Society, 29(4), 1047–1053.
Abstract: BRG1/SMARCA4 and its paralog BRM/SMARCA2 are the ATPase subunits of human SWI/SNF chromatin remodeling complexes. These multisubunit assemblies can act as either tumor suppressors or drivers of cancer, and inhibiting both BRG1 and BRM, is emerging as an effective therapeutic strategy in diverse cancers. BRG1 and BRM contain a BRK domain. The function of this domain is unknown, but it is often found in proteins involved in transcription and developmental signaling in higher eukaryotes, in particular in proteins that remodel chromatin. We report the NMR structure of the BRG1 BRK domain. It shows similarity to the glycine-tyrosine-phenylalanine (GYF) domain, an established protein-protein interaction module. Computational peptide-binding-site analysis of the BRK domain identifies a binding site that coincides with a highly conserved groove on the surface of the protein. This sets the scene for experiments to elucidate the role of this domain, and evaluate the potential of targeting it for cancer therapy.
Keywords: BAF complexes; NMR; SMARCA4 subunit; cancer; heart diseases; neurodevelopmental disorders; protein-protein interactions; structural determination
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Çötelioğlu, E., Franzoni, F., & Plazzi, A. (2020). What Constrains Liquidity Provision? Evidence from Institutional Trades*. Rev Financ, .
Abstract: The article studies liquidity provision by institutional investors using trade-level data. We find that hedge fund trades are a more important predictor of stock-level liquidity than mutual fund trades. However, hedge funds’ liquidity provision is more exposed to financial conditions than that of mutual funds. Hedge funds that are more constrained in terms of leverage, age, asset illiquidity, and past performance exhibit a stronger shift toward liquidity consumption when funding condition tighten. Stocks with more exposure to constrained liquidity providing hedge funds suffered more during the financial crisis.
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Cagliani, R., Forni, D., Clerici, M., & Sironi, M. (2020). Computational inference of selection underlying the evolution of the novel coronavirus, SARS-CoV-2. J Virol, .
Abstract: The novel coronavirus (SARS-CoV-2) recently emerged in China is thought to have a bat origin, as its closest known relative (BatCoV RaTG13) was described in horseshoe bats. We analyzed the selective events that accompanied the divergence of SARS-CoV-2 from BatCoV RaTG13. To this aim, we applied a population genetics-phylogenetics approach, which leverages within-population variation and divergence from an outgroup. Results indicated that most sites in the viral ORFs evolved under strong to moderate purifying selection. The most constrained sequences corresponded to some non-structural proteins (nsps) and to the M protein. Conversely, nsp1 and accessory ORFs, particularly ORF8, had a non-negligible proportion of codons evolving under very weak purifying selection or close to selective neutrality. Overall, limited evidence of positive selection was detected. The 6 bona fide positively selected sites were located in the N protein, in ORF8, and in nsp1. A signal of positive selection was also detected in the receptor-binding motif (RBM) of the spike protein but most likely resulted from a recombination event that involved the BatCoV RaTG13 sequence. In line with previous data, we suggest that the common ancestor of SARS-CoV-2 and BatCoV RaTG13 encoded/encodes an RBM similar to that observed in SARS-CoV-2 itself and in some pangolin viruses. It is presently unknown whether the common ancestor still exists and which animals it infects. Our data however indicate that divergence of SARS-CoV-2 from BatCoV RaTG13 was accompanied by limited episodes of positive selection, suggesting that the common ancestor of the two viruses was poised for human infection.IMPORTANCE Coronaviruses are dangerous zoonotic pathogens: in the last two decades three coronaviruses have crossed the species barrier and caused human epidemics. One of these is the recently emerged SARS-CoV-2. We investigated how, since its divergence from a closely related bat virus, natural selection shaped the genome of SARS-CoV-2. We found that distinct coding regions in the SARS-CoV-2 genome evolve under different degrees of constraint and are consequently more or less prone to tolerate amino acid substitutions. In practical terms, the level of constraint provides indications about which proteins/protein regions are better suited as possible targets for the development of antivirals or vaccines. We also detected limited signals of positive selection in three viral ORFs. However, we warn that, in the absence of knowledge about the chain of events that determined the human spill-over, these signals should not be necessarily interpreted as evidence of an adaptation to our species.
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Cagliani, R., Forni, D., Mozzi, A., & Sironi, M. (2020). Evolution and Genetic Diversity of Primate Cytomegaloviruses. Microorganisms, 8(5).
Abstract: Cytomegaloviruses (CMVs) infect many mammals, including humans and non-human primates (NHPs). Human cytomegalovirus (HCMV) is an important opportunistic pathogen among immunocompromised patients and represents the most common infectious cause of birth defects. HCMV possesses a large genome and very high genetic diversity. NHP-infecting CMVs share with HCMV a similar genomic organization and coding content, as well as the course of viral infection. Recent technological advances have allowed the sequencing of several HCMV strains from clinical samples and provided insight into the diversity of NHP-infecting CMVs. The emerging picture indicates that, with the exclusion of core genes (genes that have orthologs in all herpesviruses), CMV genomes are relatively plastic and diverse in terms of gene content, both at the inter- and at the intra-species level. Such variability most likely underlies the strict species-specificity of these viruses, as well as their ability to persist lifelong and with relatively little damage to their hosts. However, core genes, despite their strong conservation, also represented a target of adaptive evolution and subtle changes in their coding sequence contributed to CMV adaptation to different hosts. Indubitably, important knowledge gaps remain, the most relevant of which concerns the role of viral genetics in HCMV-associated human disease.
Keywords: cytomegalovirus; genome organization; non-human primates; positive selection; species-specificity
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Chen, Y., Lu, H., Zhang, N., Zhu, Z., Wang, S., & Li, M. (2020). PremPS: Predicting the impact of missense mutations on protein stability. PLoS computational biology, 16(12), e1008543.
Abstract: Computational methods that predict protein stability changes induced by missense mutations have made a lot of progress over the past decades. Most of the available methods however have very limited accuracy in predicting stabilizing mutations because existing experimental sets are dominated by mutations reducing protein stability. Moreover, few approaches could consistently perform well across different test cases. To address these issues, we developed a new computational method PremPS to more accurately evaluate the effects of missense mutations on protein stability. The PremPS method is composed of only ten evolutionary- and structure-based features and parameterized on a balanced dataset with an equal number of stabilizing and destabilizing mutations. A comprehensive comparison of the predictive performance of PremPS with other available methods on nine benchmark datasets confirms that our approach consistently outperforms other methods and shows considerable improvement in estimating the impacts of stabilizing mutations. A protein could have multiple structures available, and if another structure of the same protein is used, the predicted change in stability for structure-based methods might be different. Thus, we further estimated the impact of using different structures on prediction accuracy, and demonstrate that our method performs well across different types of structures except for low-resolution structures and models built based on templates with low sequence identity. PremPS can be used for finding functionally important variants, revealing the molecular mechanisms of functional influences and protein design. PremPS is freely available at https://lilab.jysw.suda.edu.cn/research/PremPS/, which allows to do large-scale mutational scanning and takes about four minutes to perform calculations for a single mutation per protein with \textbackslashtextasciitilde 300 residues and requires \textbackslashtextasciitilde 0.4 seconds for each additional mutation.
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Erdős, G., & Dosztányi, Z. (2020). Analyzing Protein Disorder with IUPred2A. Current Protocols in Bioinformatics, 70(1), e99.
Abstract: IUPred2A is a combined prediction tool designed to discover intrinsically disordered or conditionally disordered proteins and protein regions. Intrinsically disordered regions exist without a well‐defined three‐dimensional structure in isolation but carry out important biological functions. Over the years, various prediction methods have been developed to characterize disordered regions. The existence of disordered segments can also be dependent on different factors such as binding partners or environmental traits like pH or redox potential, and recognizing such regions represents additional computational challenges. In this article, we present detailed instructions on how to use IUPred2A, one of the most widely used tools for the prediction of disordered regions/proteins or conditionally disordered segments, and provide examples of how the predictions can be interpreted in different contexts. © 2020 The Authors. Basic Protocol 1: Analyzing disorder propensity with IUPred2A online Basic Protocol 2: Analyzing disordered binding regions using ANCHOR2 Support Protocol 1: Interpretation of the results Basic Protocol 3: Analyzing redox‐sensitive disordered regions Support Protocol 2: Download options Support Protocol 3: REST API for programmatic purposes Basic Protocol 4: Using IUPred2A locally
Keywords: computational tool
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Fernando, T. M., Piskol, R., Bainer, R., Sokol, E. S., Trabucco, S. E., Zhang, Q., et al. (2020). Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients. Nature communications, 11(1), 5551.
Abstract: Genomic studies performed in cancer patients and tumor-derived cell lines have identified a high frequency of alterations in components of the mammalian switch/sucrose non-fermentable (mSWI/SNF or BAF) chromatin remodeling complex, including its core catalytic subunit, SMARCA4. Cells exhibiting loss of SMARCA4 rely on its paralog, SMARCA2, making SMARCA2 an attractive therapeutic target. Here we report the genomic profiling of solid tumors from 131,668 cancer patients, identifying 9434 patients with one or more SMARCA4 gene alterations. Homozygous SMARCA4 mutations were highly prevalent in certain tumor types, notably non-small cell lung cancer (NSCLC), and associated with reduced survival. The large sample size revealed previously uncharacterized hotspot missense mutations within the SMARCA4 helicase domain. Functional characterization of these mutations demonstrated markedly reduced remodeling activity. Surprisingly, a few SMARCA4 missense variants partially or fully rescued paralog dependency, underscoring that careful selection criteria must be employed to identify patients with inactivating, homozygous SMARCA4 missense mutations who may benefit from SMARCA2-targeted therapy.
Keywords: Smarca4
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Forni, D., & Sironi, M. (2020). Population structure of Lassa Mammarenavirus in West Africa. Viruses, 12(4).
Abstract: Lassa mammarenavirus (LASV) is the etiologic agent of Lassa fever. In endemic regions in West Africa, LASV genetic diversity tends to cluster by geographic area. Seven LASV lineages are recognized, but the role of viral genetic determinants on disease presentation in humans is uncertain. We investigated the geographic structure and distribution of LASV in West Africa. We found strong spatial clustering of LASV populations, with two major east-west and north-south diversity gradients. Analysis of ancestry components indicated that known LASV lineages diverged from an ancestral population that most likely circulated in Nigeria, although alternative locations, such as Togo, cannot be excluded. Extant sequences carrying the largest contribution of this ancestral population include the prototype Pinneo strain, the Togo isolates, and a few viruses isolated in Nigeria. The LASV populations that experienced the strongest drift circulate in Mali and the Ivory Coast. By focusing on sequences form a single LASV sublineage (IIg), we identified an ancestry component possibly associated with protection from a fatal disease outcome. Although the same ancestry component tends to associate with lower viral loads in plasma, the small sample size requires that these results are treated with extreme caution.
Keywords: Lassa mammarenavirus; ancestry component; disease outcome; geographic distribution; population structure
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Forni, D., Cagliani, R., Clerici, M., Pozzoli, U., & Sironi, M. (2020). You Will Never Walk Alone: Codispersal of JC Polyomavirus with Human Populations. Mol Biol Evol, 37(2), 442–454.
Abstract: JC polyomavirus (JCPyV) is one of the most prevalent human viruses. Findings based on the geographic distribution of viral subtypes suggested that JCPyV codiverged with human populations. This view was however challenged by data reporting a much more recent origin and expansion of JCPyV. We collected information on approximately 1,100 worldwide strains and we show that their geographic distribution roughly corresponds to major human migratory routes. Bayesian phylogeographic analysis inferred a Subsaharan origin for JCPyV, although with low posterior probability. High confidence inference at internal nodes provided strong support for a long-standing association between the virus and human populations. In line with these data, pairwise FST values for JCPyV and human mtDNA sampled from the same areas showed a positive and significant correlation. Likewise, very strong relationships were found when node ages in the JCPyV phylogeny were correlated with human population genetic distances (nuclear-marker based FST). Reconciliation analysis detected a significant cophylogenetic signal for the human population and JCPyV trees. Notably, JCPyV also traced some relatively recent migration events such as the expansion of people from the Philippines/Taiwan area into Remote Oceania, the gene flow between North-Eastern Siberian and Ainus, and the Koryak contribution to Circum-Arctic Americans. Finally, different molecular dating approaches dated the origin of JCPyV in a time frame that precedes human out-of-Africa migration. Thus, JCPyV infected early human populations and accompanied our species during worldwide dispersal. JCPyV typing can provide reliable geographic information and the virus most likely adapted to the genetic background of human populations.
Keywords: *JC polyomavirus; *codispersal; *human populations; *molecular dating; *phylogeography
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Forni, D., Pontremoli, C., Clerici, M., Pozzoli, U., Cagliani, R., & Sironi, M. (2020). Recent Out-of-Africa Migration of Human Herpes Simplex Viruses. Mol Biol Evol, 37(5), 1259–1271.
Abstract: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous human pathogens. Both viruses evolved from simplex viruses infecting African primates and they are thus thought to have left Africa during early human migrations. We analyzed the population structure of HSV-1 and HSV-2 circulating strains. Results indicated that HSV-1 populations have limited geographic structure and the most evident clustering by geography is likely due to recent bottlenecks. For HSV-2, the only level of population structure is accounted for by the so-called “worldwide” and “African” lineages. Analysis of ancestry components and nucleotide diversity, however, did not support the view that the worldwide lineage followed early humans during out-of-Africa dispersal. Although phylogeographic analysis confirmed an African origin for both viruses, molecular dating with a method that corrects for the time-dependent rate phenomenon indicated that HSV-1 and HSV-2 migrated from Africa in relatively recent times. In particular, we estimated that the HSV-2 worldwide lineage left the continent in the 18th century, which corresponds to the height of the transatlantic slave trade, possibly explaining the high prevalence of HSV-2 in the Americas (second highest after Africa). The limited geographic clustering of HSV-1 makes it difficult to date its exit from Africa. The split between the basal clade, containing mostly African sequences, and all other strains was dated at approximately 5,000 years ago. Our data do not imply that herpes simplex viruses did not infect early humans but show that the worldwide distribution of circulating strains is the result of relatively recent events.
Keywords: Hsv-1; Hsv-2; molecular dating; phylogeography; population structure
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