bluuebunny/crossref_metadata_2025_split huggingface dataset:
High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme
Authors: Appadurai Rajeswari , Nagesh Jayashree , Srivastava Anand 
Published: June 2020

AbstractDetermining the conformational ensemble for proteins with multi-funneled complex free-energy landscapes is often not possible with classical structure-biology methods that produce time and ensemble averaged data. With vastly improved force fields and advances in rare-event sampling methods, molecular dynamics (MD) simulations offer a complementary approach towards determining the collection of 3-dimensional structures that proteins can adopt. However, in general, MD simulations need to either impose restraints or reweigh the generated data to match experiments. The limitations extend beyond systems with high free-energy barriers as is the case with metamorphic proteins such as RFA-H. The predicted structures in even weakly-funneled intrinsically disordered proteins (IDPs) such as Histatin-5 (His-5) are too compact relative to experiments. Here, we employ a new computationally-efficient parallel-tempering based advanced-sampling method applicable across proteins with extremely diverse free-energy landscapes. And we show that the calculated ensemble averages match reasonably well with the NMR, SAXS and other biophysical experiments without the need to reweigh. We benchmark our method against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin and demonstrate significant enhancement in the sampling efficiency. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as His-5 and produces experimentally-consistent ensemble. By allowing accurate sampling across diverse landscapes, the method enables for ensemble conformational sampling of deep multi-funneled metamorphic proteins as well as highly flexible IDPs with shallow multi-funneled free-energy landscape.Significance/Authors’ SummaryGenerating high-resolution ensemble of intrinsically disordered proteins, particularly the highly flexible ones with high-charge and low-hydrophobicity and with shallow multi-funneled free-energy landscape, is a daunting task and often not possible since information from biophysical experiments provide time and ensemble average data at low resolutions. At the other end of the spectrum are the metamorphic proteins with multiple deep funnels and elucidating the structures of the transition intermediates between the fold topologies is a non-trivial exercise. In this work, we propose a new parallel-tempering based advanced-sampling method where the Hamiltonian is designed to allow faster decay of water orientation dynamics, which in turn facilitates accurate and efficient sampling across a wide variety of free-energy landscapes.
Mitotic retention of H3K27 acetylation promotes rapid topological and transcriptional resetting of stem cell-related genes and enhancers upon G1 entry
Authors: Pelham-Webb Bobbie , Polyzos Alexander , Wojenski Luke , Kloetgen Andreas , Li Jiexi , Di Giammartino Dafne Campigli , Core Leighton , Tsirigos Aristotelis , Apostolou Effie 
Published: June 2020

ABSTRACTThe identity of dividing cells is challenged during mitosis, as transcription is halted and chromatin architecture drastically altered. How cell type-specific gene expression and genomic organization are faithfully reset upon G1 entry in daughter cells remains elusive. To address this issue, we characterized at a genome-wide scale the dynamic transcriptional and architectural resetting of mouse pluripotent stem cells (PSCs) upon mitotic exit. This revealed distinct patterns of transcriptional reactivation with rapid induction of stem cell genes and their enhancers, a more gradual recovery of metabolic and cell cycle genes, and a weak and transient activation of lineage-specific genes only during G1. Topological reorganization also occurred in an asynchronous manner and associated with the levels and kinetics of transcriptional reactivation. Chromatin interactions around active promoters and enhancers, and particularly super enhancers, reformed at a faster rate than CTCF/Cohesin-bound structural loops. Interestingly, regions with mitotic retention of the active histone mark H3K27ac and/or specific DNA binding factors showed faster transcriptional and architectural resetting, and chemical inhibition of H3K27 acetylation specifically during mitosis abrogated rapid reactivation of H3K27ac-bookmarked genes. Finally, we observed a contact between the promoter of an endoderm master regulator,Gata6, and a novel enhancer which was preestablished in PSCs and preserved during mitosis. Our study provides an integrative map of the topological and transcriptional changes that lead to the resetting of pluripotent stem cell identity during mitotic exit, and reveals distinct patterns and features that balance the dual requirements for self-renewal and differentiation.
miR-203 imposes an intrinsic barrier during cellular reprogramming by targeting NFATC2
Authors: Salazar-Roa María , Martínez-Martínez Sara , Graña-Castro Osvaldo , Álvarez-Fernández Mónica , Trakala Marianna , Redondo Juan-Miguel , Malumbres Marcos 
Published: June 2020

AbstractCellular reprogramming from somatic to pluripotent cells is the basis for multiple applications aimed to replace damaged tissues in regenerative medicine. However, this process is limited by intrinsic barriers that are induced in response to reprogramming factors. In this manuscript we report that miR-203, a microRNA with multiple functions in differentiation and tumor suppression, acts as an endogenous barrier to reprogramming. Genetic ablation of miR-203 results in enhanced reprogramming whereas its expression prevents the formation of pluripotent cells both in vitro and in vivo. Mechanistically, this effect correlates with the direct repression of NFATC2, a transcription factor involved in the early phases of reprogramming. Inhibition of NFATC2 mimics miR-203 effects whereas NFATC2 overexpression rescues inducible cell pluripotency in miR-203-overexpressing cultures. These data suggest that miR-203 repression may favor the efficiency of reprogramming in a variety of cellular models.
Substitution of nucleotide-sugar by trehalose-dependent glycogen synthesis pathways in Chlamydiales underlines an unusual requirement for storage polysaccharides within obligate intracellular bacteria
Authors: Colpaert Matthieu , Kadouche Derifa , Ducatez Mathieu , Pillonel Trestan , Kebbi-Beghdadi Carole , Cenci Ugo , Huang Binquan , Chabi Malika , Maes Emmanuel , Coddeville Bernadette , Couderc Loïc , Touzet Hélène , Bray Fabrice , Tirtiaux Catherine , Ball Steven , Greub Gilbert , Christophe Colleoni 
Published: June 2020

AbstractAll obligate intracellular pathogens or symbionts of eukaryotes lack glycogen metabolism. Most members of theChlamydialesorder are exceptions to this rule as they contain the classical GlgA-GlgC-dependent pathway of glycogen metabolism that relies on the ADP-Glucose substrate. We surveyed the diversity of Chlamydiales and found glycogen metabolism to be universally present with the important exception ofCriblamydiaceaeandWaddliaceaefamilies that had been previously reported to lack an active pathway. However, we now find elements of the more recently described GlgE maltose-1-P-dependent pathway in several protist-infecting Chlamydiales. In the case ofWaddliaceaeandCriblamydiaceae, the substitution of the classical pathway by this recently proposed GlgE pathway was essentially complete as evidenced by the loss of both GlgA and GlgC. Biochemical analysis of recombinant proteins expressed fromWaddlia chondrophilaandEstrella lausannensisestablished that both enzymes do polymerize glycogen from trehalose through the production of maltose-1-P by TreS-Mak and its incorporation into glycogen’s outer chains by GlgE. UnlikeMycobacteriaceaewhere GlgE-dependent polymerization is produced from both bacterial ADP-Glc and trehalose, glycogen synthesis seems to be entirely dependent on host supplied UDP-Glc and Glucose-6-P or on host supplied trehalose and maltooligosaccharides. These results are discussed in the light of a possible effector nature of these enzymes, of the chlamydial host specificity and of a possible function of glycogen in extracellular survival and infectivity of the chlamydial elementary bodies. They underline that contrarily to all other obligate intracellular bacteria, glycogen metabolism is indeed central to chlamydial replication and maintenance.
Multi-parametric disease dynamics study and analysis of the COVID-19 epidemic and implementation of population-wide intrusions: The Indian perspective
Authors: Bharti Samuel , Narad Priyanka , Chugh Parul , Choudhury Alakto , Bhatnagar Seema , Sengupta Abhishek 
Published: June 2020

AbstractThe outbreak of COVID-19 had spread at a deadly rate since its onset at Wuhan, China and is now spread across 216 countries and has affected more than 6 million people all over the world. The global response throughout the world has been primarily the implementation of lockdown measures, testing and contact tracing to minimise the spread of the disease. The aim of the present study was to predict the COVID-19 prevalence and disease progression rate in Indian scenario in order to provide an analysis that can shed light on comprehending the trends of the outbreak and outline an impression of the epidemiological stage for each state of a diverse country like India. In addition, the forecast of COVID-19 incidence trends of these states can help take safety measures and policy design for this epidemic in the days to come. In order to achieve the same, we have utilized an approach where we test modelling choices of the spatially unambiguous kind, proposed by the wave of infections spreading from the initial slow progression to a higher curve. We have estimated the parameters of an individual state using factors like population density and mobility. The findings can also be used to strategize the testing and quarantine processes to manipulate the spread of the disease in the future. This is especially important for a country like India that has several limitations about healthcare infrastructure, diversity in socioeconomic status, high population density, housing conditions, health care coverage that can be important determinants for the overall impact of the pandemic. The results of our 5-phase model depict a projection of the state wise infections/disease over time. The model can generate live graphs as per the change in the data values as the values are automatically being fetched from the crowd-sourced database.
CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition
Authors: Musicant Adele M. , Parag-Sharma Kshitij , Gong Weida , Sengupta Monideepa , Chatterjee Arindam , Henry Erin C. , Tsai Yi-Hsuan , Hayward Michele C. , Sheth Siddharth , Betancourt Renee , Hackman Trevor G. , Padilla Ricardo J. , Parker Joel S. , Giudice Jimena , Flaveny Colin A. , Hayes David N. , Amelio Antonio L. 
Published: June 2020

SUMMARYMucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which regulates PPARγ-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγinhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.
Evolutionarily related small viral fusogens hijack distinct but modular actin nucleation pathways to drive cell-cell fusion
Authors: Chan Ka Man Carmen , Arthur Ashley L. , Morstein Johannes , Jin Meiyan , Bhat Abrar , Schlesinger Dörte , Son Sungmin , Stevens Donté A. , Drubin David G. , Fletcher Daniel A. 
Published: June 2020

AbstractFusion-associated small transmembrane (FAST) proteins are a diverse family of non-structural viral proteins that, once expressed on the plasma membrane of infected cells, drive fusion with neighboring cells, increasing viral spread and pathogenicity. Unlike viral fusogens with tall ectodomains that pull two membranes together through conformational changes, FAST proteins have short fusogenic ectodomains that cannot bridge the inter-membrane gap between neighboring cells. One orthoreovirus FAST protein, p14, has been shown to hijack the actin cytoskeleton to drive cell-cell fusion, but the actin adaptor-binding motif identified in p14 is not found in any other FAST protein. Here, we report that an evolutionarily divergent FAST protein, p22 from aquareovirus, also hijacks the actin cytoskeleton but does so through different adaptor proteins, Intersectin-1 and Cdc42, that trigger N-WASP-mediated branched actin assembly. We show that despite using different pathways, the cytoplasmic tails of p22 and p14 can be exchanging to create a potent chimeric fusogen, suggesting they are modular and play similar functional roles. When we replace p22’s branched actin nucleator, N-WASP, with the parallel filament nucleator, formin, its ability to drive fusion is maintained, indicating that localized mechanical pressure on the plasma membrane coupled to a membrane-disruptive ectodomain is sufficient to drive cell-cell fusion. This work points to a common biophysical strategy used by FAST proteins to push rather than pull membranes together to drive fusion, one that may be harnessed by other short fusogens responsible for physiological cell-cell fusion.
Discovering compounds mimicking calorie restriction using mammalian gene expression profiles
Authors: Vazquez Alexei 
Published: June 2020

AbstractObesity is a risk factor for cardiovascular diseases, diabetes and cancer. In theory the obesity problem could be solve by the adherence to a calorie restricted diet, but that is not generally achieved in practice. An alternative is a pharmacological approach, using compounds that trigger the same metabolic changes associated with calorie restriction. Here I expand in the pharmacological direction by identifying compounds that induce liver gene signature profiles that mimic those induced by calorie restriction. Using gene expression profiles from mice and rat I identify corticosteroids, PPAR agonists and some antibacterial/antifungal as candidate compounds mimicking the response to calorie restriction in the liver gene signatures. Liver gene signature analysis can be used to identify compounds that mimic calorie restriction.
Novel Serine/Threonine-O-glycosylation with N-Acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid by Maf glycosyltransferases
Authors: Khairnar Aasawari , Sunsunwal Sonali , Babu Ponnusamy , Ramya T.N.C. 
Published: June 2020

AbstractSome bacterial flagellins are O-glycosylated on surface-exposed Serine/Threonine residues with nonulosonic acids such as pseudaminic acid, legionaminic acid, and their derivatives by flagellin nonulosonic acid glycosyltransferases, also called Motility associated factors (Maf). We report here two new glycosidic linkages previously unknown in any organism, Serine/Threonine-O-linked N-Acetylneuraminic acid (Ser/Thr-O-Neu5Ac) and Serine/Threonine-O-linked 3-Deoxy-D-manno-octulosonic acid (Ser/Thr-O-KDO), both catalysed byGeobacillus kaustophilusMaf (putative flagellin sialyltransferase) andClostridium botulinumMaf (putative flagellin legionaminic acid transferase). We identified these novel glycosidic linkages in recombinantG. kaustophilusandC. botulinumflagellins that were co-expressed with their cognate recombinant Maf protein inEscherichia colistrains producing the appropriate nucleotide sugar glycosyl donor. The glycosylation ofG. kaustophilusflagellin with KDO, and that ofC. botulinumflagellin with Neu5Ac and KDO indicates that Maf glycosyltransferases display donor substrate promiscuity. Maf glycosyltransferases have the potential to radically expand the scope of neoglycopeptide synthesis and posttranslational protein engineering.Significance StatementGlycosylation, the modification of proteins with sugars, is one of the most common post-translational modifications observed in proteins. While glycosylation is versatile, the most common forms of glycosylation are N-glycosylation, where the N atom of Asparagine is modified with a glycan, and O-glycosylation where the O atom of serine or threonine residues is modified with a glycan. Here, we report a novel type of O-glycosylation in the bacterial flagellin proteins of two Gram-positive bacteria,Geobacillus kaustophilusandClostridium botulinum. We demonstrate for the first time that the enzyme flagellin Maf glycosyltransferase is capable of transferring the monosaccharides, N-acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid, on to serine and threonine residues of these proteins.
The Hitchhiker’s Guide to the Periplasm: Unexpected Molecular Interactions of Antibiotics Revealed by Considering Crowding Effects inE. coli
Authors: Pedebos Conrado , Smith Iain P. S. , Boags Alister , Khalid Syma 
Published: June 2020

AbstractThe periplasm of Gram-negative bacteria is a highly crowded environment comprised of many different molecular species. Antibacterial agents that causes lysis of Gram-negative bacteria by their action against the inner membrane must cross the periplasm to arrive at their target membrane. Very little is currently known about their route through the periplasm, and the interactions they experience. To this end, here atomistic molecular dynamics simulations are used to study the path taken by the antibiotic polymyxin B1 through a number of models of the periplasm which are crowded with proteins and osmolytes to different extents. The simulations reveal that PMB1 forms transient and long-lived interactions with proteins and osmolytes that are free in solution as well as lipoproteins anchored to the outer membrane and bound to the cell wall. We show that PMB1 may be able to ‘hitchhike’ within the periplasm by binding to lipoprotein carriers. Overall our results show that PMB1 is rarely uncomplexed within the periplasm; an important consideration for interpretations of its therapeutic mechanism of action. It is likely that this observation can be extended to other antibiotics that rely on diffusion to cross the periplasm.
The inhibitory effect of a Corona virus spike protein fragment with ACE2
Authors: Peter E. K. , Schug A. 
Published: June 2020

ABSTRACTIn this paper, we investigate the molecular assembly processes of a Coronavirus Spike protein fragment, the hexapeptide YKYRYL on the ACE2 receptor and its inhibitory effect on the aggregation and activation of the CoV-2 spike receptor protein at the same receptor protein. In agreement with an experimental study, we find a high affinity of the hexapeptide to the binding interface between the spike receptor protein and ACE2, which we investigate using 20 independent equilibrium MD simulations over a total of 1μs and a 200 ns enhanced MD simulation. We then evaluate the effect of the hexapeptide on the aggregation process of the spike receptor protein to ACE2 in long-time enhanced MD simulations. In that set of simulations, we find that the spike receptor protein does not bind to ACE2 with the binding motif shown in experiments, but it rotates due to an electrostatic repulsion and forms a hydrophobic interface with ACE2. Surprisingly, we observe that the hexapeptide binds to the spike receptor domain, which has the effect that this protein only weakly attaches to ACE2, so that the activation of the spike protein receptor might be inhibited in this case. Our results indicate that the hexapeptide might be a possible treatment option which prevents the viral activation through the inhibition of the interaction between ACE2 and the spike receptor protein.SIGNIFICANCEA novel coronavirus, CoV-19 and a later phenotype CoV-2 were identified as primary cause for a severe acute respiratory syndrome (SARS CoV-2). The spike (S) protein of CoV-2 is one target for the development of a vaccine to prevent the viral entry into human cells. The inhibition of the direct interaction between ACE2 and the S-protein could provides a suitable strategy to prevent the membrane fusion of CoV-2 and the viral entry into human cells. Using MD simulations, we investigate the assembly process of a Coronavirus Spike protein fragment, the hexapeptide YKYRYL on the ACE2 receptor and its inhibitzory effect on the aggregation and activation of the CoV-2 spike receptor protein at the same receptor protein.
Transcranial ultrasonic propagation and enhanced brain imaging exploiting the focusing effect of the skull
Authors: Amanatiadis Stamatis A. , Apostolidis Georgios K. , Bekiari Chrysanthi S. , Kantartzis Nikolaos V. 
Published: June 2020

Purpose
The reliable transcranial imaging of brain inner structures for diagnostic purposes is deemed crucial owing to the decisive importance and contribution of the brain in human life. The purpose of this paper is to investigate the potential application of medical ultrasounds to transcranial imaging using advanced techniques, such as the total focussing method.

Design/methodology/approach
Initially, the fundamental details of the total focussing method are presented, while the skull properties, such as the increased acoustic velocity and scattering, are thoroughly examined. Although, these skull characteristics constitute the main drawback of typical transcranial ultrasonic propagation algorithms, they are exploited to focus the acoustic waves towards the brain. To this goal, a virtual source is designed, considering the wave refraction, to efficiently correct the reconstructed brain image. Finally, the verification of the novel method is conducted through numerical simulations of various realistic setups.

Findings
The theoretically designed virtual source resembles a focussed sensor; therefore, the directivity increment, owing to the propagation through the skull, is confirmed. Moreover, numerical simulations of real-world scenarios indicate that the typical artifacts of the conventional total focussing method are fully overcome because of the increased directivity of the proposed technique, while the reconstructed image is efficiently corrected when the proposed virtual source is used.

Originality/value
A new systematic methodology along with the design of a flexible virtual source is developed in this paper for the reliable and precise transcranial ultrasonic image reconstruction of the brain. Despite the slight degradation owing to the skull scattering, the combined application of the total focussing method and the featured virtual source can successfully detect arbitrary anomalies in the brain that cannot be spotted by conventional techniques.