Miracle-dz/UniFAR-FTUs huggingface dataset:
Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases

Influenza A virus and coronavirus strains cause a mild to severe respiratory disease that can result in death. Although vaccines exist against circulating influenza A viruses, such vaccines are ineffective against emerging pandemic influenza A viruses. Currently, no vaccine exists against coronavirus infections, including pandemic SARS-CoV-2, the causative agent of the Coronavirus Disease 2019 (COVID-19). To combat these RNA virus infections, alternative antiviral strategies are needed. A key drug target is the viral RNA polymerase, which is responsible for viral RNA synthesis. In January 2020, the World Health Organisation identified enisamium as a candidate therapeutic against SARS-CoV-2. Enisamium is an isonicotinic acid derivative that is an inhibitor of multiple influenza B and A virus strains in cell culture and clinically approved in 11 countries. Here we show using in vitro assays that enisamium and its putative metabolite, VR17-04, inhibit the activity of the influenza virus and the SARS-CoV-2 RNA polymerase. VR17-04 displays similar efficacy against the SARS-CoV-2 RNA polymerase as the nucleotide analogue remdesivir triphosphate. These results suggest that enisamium is a broad-spectrum small molecule inhibitor of RNA virus RNA synthesis, and implicate it as a possible therapeutic option for treating SARS-CoV-2 infection. Unlike remdesivir, enisamium does not require intravenous administration which may be advantageous for the development of COVID-19 treatments outside a hospital setting. Importance Influenza A virus and SARS-CoV-2 are respiratory viruses capable of causing pandemics, and the latter is responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. Both viruses encode RNA polymerases which transcribe their RNA genomes and are important targets for antiviral drugs including remdesivir. Here, we show that the antiviral drug enisamium inhibits the RNA polymerases of both influenza A virus and SARS-CoV-2. Furthermore, we show that a putative metabolite of enisamium is a more potent inhibitor, inhibiting the SARS-CoV-2 RNA polymerase with similar efficiency to remdesivir. Our data offer insight into the mechanism of action for enisamium, and implicate it as a broad-spectrum antiviral which could be used in the treatment of SARS-CoV-2 infection.
Ribosome profiling in Mycobacterium tuberculosis reveals robust leaderless translation

Mycobacterium tuberculosis, which causes tuberculosis, expresses a large proportion of leaderless transcripts lacking the canonical bacterial translation initiation signals. The role leaderless genes play in the physiology of this pathogen, which can undergo prolonged periods of non-replicating persistence in the host, is currently unknown. We have previously demonstrated that levels of leaderless transcription increase under conditions of nutrient starvation. However, little is known about the implications of this for persistent infection. Here, we performed ribosome profiling to characterise the translational landscape of M. tuberculosis in vitro. Our data reveals robust leaderless translation in the pathogen and points towards different mechanisms for their initiation of translation compared to canonical Shine-Dalgarno genes. Furthermore, under conditions of nutrient starvation, we found a significant global up-regulation of leaderless genes in the translatome. Our data represents a rich resource for others seeking to understand translational regulation not only in M. tuberculosis but in bacterial pathogens.
A scientometric overview of CORD-19

As the COVID-19 pandemic unfolds, researchers from all disciplines are coming together and contributing their expertise. CORD-19, a dataset of COVID-19 and coronavirus publications, has recently been made available alongside calls to help mine the information it contains and to create tools to search it more effectively. We analyse the delineation of the publications included in CORD-19 from a scientometric perspective. Based on a comparison to the Web of Science database, we find that CORD-19 provides an almost complete coverage of research on COVID-19 and coronaviruses. However, CORD-19 contains not only research that deals directly with COVID-19 and coronaviruses, but also research on viruses in general. Publications from CORD-19 focus mostly on a few well-defined research areas, in particular: coronaviruses (primarily SARS, MERS, COVID-19); public health and viral epidemics; molecular biology of viruses; influenza and other families of viruses; immunology and antivirals; clinical medicine. CORD-19 publications that appeared in 2020, especially editorials and letters, are disproportionately popular on social media. While we fully endorse the CORD-19 initiative, it is important to be aware that CORD-19 extends beyond research on COVID-19 and coronaviruses.
Particle-associated and free-living bacterial communities in an oligotrophic sea are affected by different environmental and anthropogenic factors

In the oceans and seas, environmental conditions change over multiple temporal and spatial scales. Here, we ask what factors affect the bacterial community structure across time, depth and size fraction during six seasonal cruises (two years) in the ultra-oligotrophic Eastern Mediterranean Sea. The bacterial community varied most between size fractions (free-living vs particle-associated), followed by depth and finally season. The free-living (FL) community was taxonomically richer and more stable than the particle-associated (PA) one, which was characterized by recurrent “blooms” of heterotrophic bacteria such as Alteromonas and Ralstonia. The heterotrophic FL and PA communities were also correlated with different environmental parameters: depth and phytoplankton correlated with the FL population, whereas PA bacteria were correlated primarily with season. A significant part of the variability in community structure could not, however, be explained by the measured environmental parameters. The metabolic potential of the PA community, predicted from 16S amplicon data, was enriched in pathways associated with the degradation and utilization of biological macromolecules, as well as plastics, other petroleum products and herbicides. The FL community was enriched in pathways for the metabolism of inositol phosphate, a potential phosphorus source, and of polycyclic aromatic hydrocarbons. Originality – Significance Statement Marine microbial populations are complex and dynamic, and the environmental drivers of the structure and function of these communities are mostly unclear. Specifically, marine microbial communities change over time, over depth and between particle-associated and free-living size fractions, yet the relative importance of each of these axes of variability is unclear. Our results highlight fundamentally different population dynamics between free-living and particle-associated marine bacteria: free living populations were more similar between seasons, whereas particle-associated populations were highly variable and exhibited “blooms” of specific clades of heterotrophic bacteria. We also suggest that the environmental conditions often measured as part of oceanographic cruises are not enough to explain most of the variability in microbial population structure. We speculate that organismal interactions and the presence of anthropogenic pollution may be also be important yet under-sampled drivers of oligotrophic marine microbial communities.
Fluorescence and Light Scatter Calibration Allow Comparisons of Small Particle Data in Standard Units across Different Flow Cytometry Platforms and Detector Settings

Flow cytometers have been utilized for the analysis of submicron‐sized particles since the late 1970s. Initially, virus analyses preceded extracellular vesicle (EV), which began in the 1990s. Despite decades of documented use, the lack of standardization in data reporting has resulted in a growing body of literature that cannot be easily interpreted, validated, or reproduced. This has made it difficult for objective assessments of both assays and instruments, in‐turn leading to significant hindrances in scientific progress, specifically in the study of EVs, where the phenotypic analysis of these submicron‐sized vesicles is becoming common‐place in every biomedical field. Methods for fluorescence and light scatter standardization are well established and the reagents to perform these analyses are commercially available. However, fluorescence and light scatter calibration are not widely adopted by the small particle community as methods to standardize flow cytometry (FCM) data. In this proof‐of‐concept study carried out as a resource for use at the CYTO2019 workshop, we demonstrate for the first‐time simultaneous fluorescence and light scatter calibration of small particle data to show the ease and feasibility of this method for standardized FCM data reporting. This data was acquired using standard configuration commercial flow cytometers, with commercially available materials, published methods, and freely available software tools. We show that application of light scatter, fluorescence, and concentration calibration can result in highly concordant data between FCM platforms independent of instrument collection angle, gain/voltage settings, and flow rate; thus, providing a means of cross comparison in standard units. © 2020 International Society for Advancement of Cytometry
Dynamical asymmetry exposes 2019-nCoV prefusion spike

The novel coronavirus (2019-nCoV) spike protein is a smart molecular machine that instigates the entry of coronavirus to the host cell causing the COVID-19 pandemic. In this study, a structural-topology based model Hamiltonian of C3 symmetric trimeric spike is developed to explore its complete conformational energy landscape using molecular dynamic simulations. The study finds 2019-nCoV to adopt a unique strategy by undertaking a dynamic conformational asymmetry induced by a few unique inter-chain interactions. This results in two prevalent asymmetric structures of spike where one or two spike heads lifted up undergoing a dynamic transition likely to enhance rapid recognition of the host-cell receptor turning on its high-infectivity. The crucial interactions identified in this study are anticipated to potentially affect the efficacy of therapeutic targets. One Sentence Summary Inter-chain-interaction driven rapid symmetry breaking strategy adopted by the prefusion trimeric spike protein likely to make 2019-nCoV highly infective.
Escherichia coli small heat shock protein IbpA is an aggregation-sensor that self-regulates its own expression at a translational level

Aggregation is an inherent characteristic of proteins. Risk management strategies to reduce aggregation are critical for cells to survive upon stresses that induce aggregation. Cells cope with protein aggregation by utilizing a variety of chaperones, as exemplified by heat-shock proteins (Hsps). The heat stress-induced expression of IbpA and IbpB, small Hsps in Escherichia coli, is regulated by the σ32 heat-shock transcriptional regulator and the temperature-dependent translational regulation via mRNA heat fluctuation. We found that, even without heat stress, either the expression of aggregation-prone proteins or the ibpA gene deletion profoundly increases the expression of IbpA. Combined with other evidence, we propose novel mechanisms for the regulation of the small Hsp expression. Oligomeric IbpA self-represses the ibpA/ibpB expression at the translational level, but the self-repression is relieved by the sequestration of IbpA into protein aggregates. Thus, the function of IbpA as a chaperone to form co-aggregates is harnessed as an aggregation sensor to tightly regulate the IbpA level. Since the excessive preemptive supply of IbpA in advance of stress is harmful, the prodigious and rapid expression of IbpA/IbpB on demand is necessary for IbpA to function as a first line of defense against acute protein aggregation. Author summary All organisms have protein quality control systems against stresses disturbing cellular protein homeostasis (proteostasis). The systems have multiple stages: folding, degradation, and sequestration. Sequestration of denatured proteins is the first step to support other maintenance strategies. Small heat shock proteins (sHsps), which are well-conserved chaperones, are representative “sequestrases” that co-aggregate with denatured proteins. We found that IbpA, an Escherichia coli sHsp, is a direct mediator for negative feedback regulation at the translational level. Recruitment of IbpA into the protein aggregates relieves the ibpA expression suppression. This novel mechanism of IbpA as an aggregation-sensor tightly regulates the IbpA level, enabling the sHsp to function as a sequestrase upon aggregation stress.
Tendon and motor phenotypes in the Crtap-/- mouse model of recessive osteogenesis imperfecta

Osteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass with bone fragility, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon/ligament dysfunction in OI pathogenesis is largely unknown. Using the Crtap-/- mouse model of severe, recessive OI, we found that mutant Achilles tendons and patellar ligaments were thinner with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar ligaments from Crtap-/- mice also had fewer progenitors with a concomitant increase in immature cells. RNA-seq analysis of Achilles tendons and patellar ligaments from 1-month Crtap-/- mice revealed dysregulation in matrix gene expression concomitant with predicted alterations in TGF-β, inflammatory, and metabolic signaling. Finally, a series of behavioral tests revealed severe motor impairments and reduced grip strength in 4-month Crtap-/- mice – a phenotype that correlates with the tendon/ligament pathology.
A General 3D Model for Growth Dynamics of Sensory-Growth Systems: From Plants to Robotics

In recent years there has been a rise in interest in the development of self-growing robotics inspired by the moving-by-growing paradigm of plants. In particular, climbing plants capitalize on their slender structures to successfully negotiate unstructured environments, while employing a combination of two classes of growth-driven movements: tropic responses, which direct growth in the direction of an external stimulus, and inherent nastic movements, such as periodic circumnutations, which promote exploration. In order to emulate these complex growth dynamics in a 3D environment, a general and rigorous mathematical framework is required. Here we develop a general 3D model for rod-like organs adopting the Frenet-Serret frame, providing a useful framework from the standpoint of robotics control. Differential growth drives the dynamics of the organ, governed by both internal and external cues. We describe the numerical method required to implement this model, and perform numerical simulations of a number of key scenarios, showcasing the applicability of our model. In the case of responses to external stimuli, we consider a distant stimulus (such as sunlight and gravity), a point stimulus (a point light source), and a line stimulus which emulates twining of a climbing plant around a support. We also simulate circumnutations, the response to an internal oscillatory cue, associated with search processes. Lastly we also demonstrate the superposition of both the response to an external stimulus together with circumnutations. Lastly we consider a simple example illustrating the possible use of an optimal control approach in order to recover tropic dynamics, in a way which may be relevant for robotics use. In all, the model presented here is general and robust, paving the way for a deeper understanding of plant response dynamics, as well as novel control systems for newly developed self-growing robots.
Reference-free and de novo Identification of Circular RNAs

Background Early studies have unveiled multiple regulatory functions of circular RNAs (circRNAs); however, accurate detection and quantification of circRNAs, especially in understudied organisms, is unsolved yet. Results In this study, we developed a new reference-free method, namely Cirit, to de novo detect circRNAs with sequence support from the next generation sequencing (NGS) transcriptome. The Cirit showed remarkable performance in accurate detection and quantification of circRNAs via comparing with current methods from different aspects. Using Cirit, we detected 28,813 nonredundant human circRNAs from 91 transcriptome datasets, as well as 2,385 circRNAs from four understudied organisms. Subsequent analyses found that the majority of human circRNAs expressed spatiotemporally; only a very small portion of circRNAs were back-splice junction (BSJ)-consistent (maximally 5.17%) or sequence-consistent (under 2%). Furthermore, circRNA genesis were relatively flexible that only about 60% of human circRNAs used the canonical GT-AG pattern for back-splice. The inconsistent expression of circRNAs challenges their roles as precise transcriptional regulators. Conclusions In summary, the reference-free method provides a straightforward and universal way for reliable circRNA research. It will largely boost the successful rate in designing highly specific probes to monitor circRNA behavior in cell. In particular, it brings circRNA research to the organisms that have no genome or draft genome.
Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity

Influenza virus infections cause a wide variety of outcomes, from mild disease to 3-5 million cases of severe illness and ~290,000-645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity. SIGNIFICANCE Influenza virus infection causes a range of outcomes from mild illness to death. The molecular mechanisms leading to these differential host responses are currently unknown. Herein, we identify the induction of high mannose, a glycan epitope, as a key mediator of severe disease outcome. We propose a mechanism in which activation of the unfolded protein response (UPR) upon influenza virus infection turns on expression of high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and leading to subsequent inflammation. This work is the first to systematically study host glycomic changes in response to influenza virus infection, identifying high mannose as a key feature of differential host response.
Natural variation in autumn FLC levels, rather than epigenetic silencing, aligns vernalization to different climates

Plants monitor temperatures over long timescales to assess seasons and time developmental transitions. In Arabidopsis thaliana, winter is registered during vernalization through the temperature-dependent repression and epigenetic silencing of floral repressor FLOWERING LOCUS C (FLC). Natural Arabidopsis accessions show considerable variation in vernalization, however which aspect of the FLC repression mechanism is most important for adaptation to different climates is not clear. By analyzing FLC silencing in natural variants throughout winter in three field sites, we find that FLC starting levels and early phases of silencing are the major variables underlying vernalization response, rather than establishment of epigenetic silencing. This results in an intricate interplay between promotion and delay of flowering to balance survival, and through a post-vernalization effect of FLC, reproductive effort via branch production. These data reveal how non-coding FLC variation aligns vernalization response to different climatic conditions and year-on-year fluctuations in natural temperature profiles. Impact Statement Alleles of the major floral repressor vary in their initial expression to underpin the ability of Arabidopsis to survive year-on-year climatic fluctuations.
Generation of cardiac valve endocardial like cells from human pluripotent stem cells

The cardiac valvular endothelial cells (VECs) are an ideal cell source that could be used for the fabrication of the next generation tissue-engineered cardiac valves (TEVs). However, few studies have been focused on the derivation of this important cell type. Here we describe a chemically defined xeno-free method for generating VEC-like cells from human pluripotent stem cells (hPSCs) through an intermediate endocardium stage. HPSCs were initially specified to KDR+/ISL1+ multipotent cardiac progenitor cells (CPCs), followed by differentiation into endocardial progenitors under the combined treatment with VEGFA, BMP4 and bFGF. In the presence of VEGFA, BMP4 and TGFb, valve endocardial progenitor cells (VEPs) were efficiently derived from endocardial progenitors without a sorting step. Mechanistically, administration of TGFb and BMP4 may specify the VEP fate by facilitating the expression of key transcription factors ETV2 and NFATc1 at the immediate early stage and by activating Notch signaling at the later stage. Notch activation is likely an important part of VEP induction. HPSC-derived VEPs exhibited morphological, molecular and functional similarities to that of the primary VECs isolated from normal human aortic valves. When hPSC-derived VEPs were seeded onto the surface of the de-cellularized porcine aortic valve (DCV) matrix scaffolds, they exhibited higher proliferation and survival potential than the primary VECs. Our results suggest that hPSC-derived VEPs could serve as as a potential platform for the study of valve development, and as starting materials for the construction of the next generation TEVs. Highlights Valve endocardial progenitor cells (VEPs) could be efficiently derived from hPSCs without a sorting step The combined treatment with TGFb and BMP4 induce VEP fate by enhancing the expression of ETV2 and NFATc1 HPSC-derived VEPs resemble the isolated primary VECs molecularly, morphologically and functionally HPSC-derived VEPs exhibit proliferative and functional potential similar to the primary VECs when seeded onto the DCVs