bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad domains of histone marks in the highly compact Paramecium macronuclear genome
Authors: Drews Franziska , Salhab Abdulrahman , Karunanithi Sivarajan , Cheaib Miriam , Jung Martin , Schulz Marcel H. , Simon Martin 
Published: August 2021

AbstractThe unicellular ciliate Paramecium contains a large vegetative macronucleus with several unusual characteristics including an extremely high coding density and high polyploidy. As macronculear chromatin is devoid of heterochromatin our study characterizes the functional epigenomic organisation necessary for gene regulation and proper PolII activity. Histone marks (H3K4me3, H3K9ac, H3K27me3) revealed no narrow peaks but broad domains along gene bodies, whereas intergenic regions were devoid of nucleosomes. Our data implicates H3K4me3 levels inside ORFs to be the main factor to associate with gene expression and H3K27me3 appears to occur as a bistable domain with H3K4me3 in plastic genes. Surprisingly, silent and lowly expressed genes show low nucleosome occupancy suggesting that gene inactivation does not involve increased nucleosome occupancy and chromatin condensation. Due to a high occupancy of Pol II along highly expressed ORFs, transcriptional elongation appears to be quite different to other species. This is supported by missing heptameric repeats in the C-terminal domain of Pol II and a divergent elongation system. Our data implies that unoccupied DNA is the default state, whereas gene activation requires nucleosome recruitment together with broad domains of H3K4me3. This could represent a buffer for paused Pol II along ORFs in absence of elongation factors of higher eukaryotes.
σ28-dependent small RNA regulation of flagella biosynthesis
Authors: Melamed Sahar , Zhang Aixia , Jarnik Michal , Mills Joshua , Silverman Aviezer , Zhang Hongen , Storz Gisela 
Published: August 2021

AbstractFlagella are important for bacterial motility as well as for pathogenesis. Synthesis of these structures is energy intensive and, while extensive transcriptional regulation has been described, little is known about the posttranscriptional regulation. Small RNAs (sRNAs) are widespread posttranscriptional regulators, most base pairing with mRNAs to affect their stability and/or translation. Here we describe four UTR-derived sRNAs (UhpU, MotR, FliX and FlgO) whose expression is controlled by the flagella sigma factor σ28(fliA) inEscherichia coli. Interestingly, the four sRNAs have varied effects on flagellin protein levels, flagella number and cell motility. UhpU, corresponding to the 3’ UTR of a metabolic gene, likely has hundreds of targets including a transcriptional regulator at the top flagella regulatory cascade connecting metabolism and flagella synthesis. Unlike most sRNAs, MotR and FliX base pair within the coding sequences of target mRNAs and act on ribosomal protein mRNAs connecting ribosome production and flagella synthesis. The study shows how sRNA-mediated regulation can overlay a complex network enabling nuanced control of flagella synthesis.
The mycobacterial guaB1 gene encodes a guanosine 5’-monophosphate reductase with a cystathione-β-synthase domain
Authors: Knejzlík Zdeněk , Doležal Michal , Herkommerová Klára , Clarova Kamila , Klíma Martin , Dedola Matteo , Zborníková Eva , Rejman Dominik , Pichová Iva 
Published: August 2021

AbstractPurine metabolism plays a pivotal role in bacterial life cycle, however, regulation of thede novoand purine salvage pathways have not been extensively detailed in mycobacteria. By gene knockout, biochemical and structural analyses, we identifiedMycobacterium smegmatis(Msm) andMycobacterium tuberculosis(Mtb)guaB1gene product as a novel type of guanosine 5’-monophosphate reductase (GMPR), which recycles guanosine monophosphate to inosine monophosphate within the purine salvage pathway and contains cystathione β-synthase (CBS) domains with atypical orientation in the octamer. CBS domains share a much larger interacting area with a conserved catalytic domain in comparison with the only known CBS containing protozoan GMPR and closely related inosine monophosphate dehydrogenase structures. Our results revealed essential effect of pH on allosteric regulation of Msm GMPR activity and oligomerization with adenine and guanosine nucleotides binding to CBS domains.Bioinformatic analysis indicated the presence of GMPRs containing CBS domains across the entireActinobacteriaphylum.
The synergistic effect of circRNA methylation promotes pulmonary fibrosis
Authors: Wang Sha , Luo Wei , Huang Jie , Chen Menglin , Ding Jiawei , Cheng Yusi , Zhang Wei , Fang Shencun , Wang Jing , Chao Jie 
Published: August 2021

AbstractRationaleN6-Methyladenosine (m6A) is the most common type of RNA methylation modification, mainly occurring on mRNA. Whether m6A-modified circRNAs are involved in different settings of pulmonary fibrosis remains unclear.Methods and ResultsUsing an m6A-circRNA epitranscriptomic chip, candidate circRNAs were selected, in which hsa_circ_0000672 and hsa_circ_0005654 were specifically involved in SiO2-induced pulmonary fibrosis by targeting the same protein, eIF4A3, indicating that the m6A modification of these two circRNAs has a synergistic effect on fibroblast dysfunction induced by SiO2. A mechanistic study revealed that the m6A modification of circRNAs was mainly mediated by the methyltransferase METTL3. Furthermore, METTL3 promoted the activation, migration and activity of pulmonary fibroblasts and participated in SiO2-induced pulmonary fibrosis via circRNA m6A modification.Conclusionm6A methylation of circRNAs mediates silica-induced fibrosis via synergistic effects, enriching the understanding of circRNAs and uncovering a potential new target to treat fibrosis-related diseases.
Mixed matrix factorization: a novel algorithm for the extraction of kinematic-muscular synergies
Authors: Scano Alessandro , Mira Robert Mihai , d’Avella Andrea 
Published: August 2021

AbstractSynergistic models have been employed to investigate motor coordination separately in the muscular and kinematic domains. However, the relationship between muscle synergies, constrained to be non-negative, and kinematic synergies, whose elements can be positive and negative, has received limited attention. Existing algorithms for extracting synergies from combined kinematic and muscular data either do not enforce non-negativity constraints or separate non-negative variables into positive and negative components. We propose a mixed matrix factorization (MMF) algorithm based on a gradient descent update rule which overcomes these limitations. It allows to directly assess the relationship between kinematic and muscle activity variables, by enforcing the non-negativity constrain on a subset of variables. We validated the algorithm on simulated kinematic-muscular data generated from known spatial synergies and temporal coefficients, by evaluating the similarity between extracted and ground truth synergies and temporal coefficients when the data are corrupted by different noise levels. We also compared the performance of MMF to that of non-negative matrix factorization applied to separate positive and negative components (NMFpn). Finally, we factorized kinematic and EMG data collected during upper-limb movements to demonstrate the potential of the algorithm. MMF achieved almost perfect reconstruction on noiseless simulated data. It performed better than NMFpn in recovering the correct spatial synergies and temporal coefficients with noisy simulated data. It also allowed to correctly select the original number of ground truth synergies. We showed meaningful applicability to real data; MMF can also be applied to any multivariate data that contains both non-negative and unconstrained variables.
Active Sinking Particles: Sessile Suspension Feeders significantly alter the Flow and Transport to Sinking Aggregates
Authors: Krishnamurthy Deepak , Pepper Rachel , Prakash Manu 
Published: August 2021

AbstractSinking or sedimentation of biological aggregates plays a critical role in carbon sequestration in the ocean and in vertical material fluxes in waste-water treatment plants. In both these contexts, the sinking aggregates are “active,” since they are biological hot-spots and are densely colonized by microorganisms including bacteria and sessile protists, some of which generate feeding currents. However, the effect of these feeding currents on the sinking rates, trajectories, and mass transfer to these “active sinking particles,” has not previously been studied. Here we use a novel scale-free vertical-tracking microscope (a.k.a. Gravity Machine, Krishnamurthy et al. “Scale-free vertical tracking microscopy.” Nature Methods (2020)) to follow model sinking aggregates (agar spheres) with attached protists (Vorticella convallaria), sinking over long distances while simultaneously measuring local flows. We find that activity due to attached Vorticella cause substantial changes to the flow around aggregates in a dynamic manner and reshape mass transport boundary layers. Further, we find that activity-mediated local flows along with sinking significantly changes how aggregates interact with the water-column at larger scales by modifying the encounter and plume cross-sections and by inducing sustained aggregate rotations. In this way our work suggests an important role of biological activity in understanding the growth, degradation, composition and sinking speeds of aggregates with consequences for predicting vertical material fluxes in marine, freshwater and man-made environments.1Significance StatementSinking aggregates are a critical part of aquatic ecosystems. Plentiful sinking aggregates account for the majority of carbon sequestration in the oceans. These aggregates are densely colonized by microorganisms, including many that generate feeding currents. Utilizing a novel instrument for high resolution imaging of sinking particles, we demonstrate that these feeding currents significantly change how water flows near the aggregates. We show that these changes in flow are likely to affect aquatic system processes, including aggregation rates, degradation rates, sinking speeds, and aggregate composition. Our work provides a starting point for exploring the larger-scale implications of attached organisms on these system processes, which, in turn, are critical for understanding carbon sequestration in the oceans or efficiency in waste-water treatment plants.
Global emergence and dissemination of Neisseria gonorrhoeae ST-9363 isolates with reduced susceptibility to azithromycin
Authors: Joseph Sandeep J. , Thomas Jesse C. , Schmerer Matthew W. , Cartee Jack , St Cyr Sancta , Schlanger Karen , Kersh Ellen N. , Raphael Brian H. , Gernert Kim M ,   Antimicrobial Resistant Neisseria gonorrhoeae Working Group.
Published: August 2021

AbstractNeisseria gonorrhoeae multi-locus sequence type (ST) 9363 genogroup isolates have been associated with reduced azithromycin susceptibility (AZMrs) and show evidence of clonal expansion in the U.S. Here we analyze a global collection of ST-9363 genogroup genomes to shed light on the emergence and dissemination of this strain. The global population structure of ST-9363 genogroup falls into three lineages: Basal, European, and North American; with 32 clades within all lineages. Although, ST-9363 genogroup is inferred to have originated from Asia in the mid-19th century; we estimate the three modern lineages emerged from Europe in the late 1970s to early 1980s. The European lineage appears to have emerged and expanded from around 1986 to 1998, spreading into North America and Oceania in the mid-2000s with multiple introductions, along with multiple secondary reintroductions into Europe. Our results suggest two separate acquisition events of mosaic mtrR and mtrR promoter alleles: first during 2009-2011 and again during the 2012-2013 time, facilitating the clonal expansion of this genogroup with AZMrs in the U.S. By tracking phylodynamic evolutionary trajectories of clades that share distinct demography as well as population-based genomic statistics, we demonstrate how recombination and selective pressures in the mtrCDE efflux operon granted a fitness advantage to establish ST-9363 as a successful gonococcal lineage in the U.S. and elsewhere. Although it is difficult to pinpoint the exact timing and emergence of this young genogroup, it remains critically important to continue monitoring it, as it could acquire additional resistance markers.
Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin
Authors: Zhang Lin , Li Ling , Wang Xia , Liu Huimin , Zhang Yibin , Xie Tiantian , Zhang Hui , Li Xiaodong , Peng Tianhuan , Sun Xing , Dai Jing , Liu Jing , Wu Wencan , Ye Mao , Tan Weihong 
Published: August 2021

AbstractPROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and have poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.
Vaccination with B.1.1.7, B.1.351 and P.1 variants protects mice from challenge with wild type SARS-CoV-2
Authors: Amanat Fatima , Strohmeier Shirin , Meade Philip , Dambrauskas Nicholas , Mühlemann Barbara , Smith Derek J. , Vigdorovich Vladimir , Sather D. Noah , Coughlan Lynda , Krammer Florian 
Published: August 2021

AbstractVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been highly efficient in protecting against coronavirus disease 2019 (COVID-19). However, the emergence of viral variants that are more transmissible and, in some cases, escape from neutralizing antibody responses has raised concerns. Here, we evaluated recombinant protein spike antigens derived from wild type SARS-CoV-2 and from variants B.1.1.7, B.1.351 and P.1 for their immunogenicity and protective effect in vivo against challenge with wild type SARS-CoV-2 in the mouse model. All proteins induced high neutralizing antibodies against the respective viruses but also induced high cross-neutralizing antibody responses. The decline in neutralizing titers between variants was moderate, with B.1.1.7 vaccinated animals having a maximum fold reduction of 4.8 against B.1.351 virus. P.1 induced the most cross-reactive antibody responses but was also the least immunogenic in terms of homologous neutralization titers. However, all antigens protected from challenge with wild type SARS-CoV-2 in a mouse model.Author SummaryThe emergence of variants of SARS-CoV-2 has led to an urgency to study whether vaccines will lead to cross-protection against these variants. Here, we demonstrate that vaccination with spike proteins of various variants leads to cross-neutralizing responses, as well as protection in a mouse model against wild type SARS-CoV-2.
GC content but not nucleosome positioning directly contributes to intron-splicing efficiency in Paramecium
Authors: Gnan Stefano , Matelot Mélody , Weiman Marion , Arnaiz Olivier , Guérin Frédéric , Sperling Linda , Bétermier Mireille , Thermes Claude , Chen Chun-Long , Duharcourt Sandra 
Published: August 2021

ABSTRACTEukaryotic genes are interrupted by introns that must be accurately spliced from mRNA precursors. With an average length of 25 nt, the >90,000 introns of Paramecium tetraurelia stand among the shortest introns reported in eukaryotes. The mechanisms specifying the correct recognition of these tiny introns remain poorly understood. Splicing can occur co-transcriptionally and it has been proposed that chromatin structure might influence splice site recognition. To investigate the roles of nucleosome positioning in intron recognition, we determined the nucleosome occupancy along the P. tetraurelia genome. We showed that P. tetraurelia displays a regular nucleosome array with a nucleosome repeat length of ∼151 bp, amongst the smallest periodicities reported. Our analysis revealed that introns are frequently associated with inter-nucleosomal DNA, pointing to an evolutionary constraint to locate introns at the AT-rich nucleosome edge sequences. Using accurate splicing efficiency data from cells depleted for the nonsense-mediated decay effectors, we showed that introns located at the edge of nucleosomes display higher splicing efficiency than those at the centre. However, multiple regression analysis indicated that the GC content, rather than nucleosome positioning, directly contributes to intron splicing efficiency. Our data reveal a complex link between GC content, nucleosome positioning and intron evolution in Paramecium.
Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair
Authors: Sigismondo Gianluca , Arseni Lavinia , Palacio-Escat Nicolàs , Hofmann Thomas G , Seiffert Martina , Krijgsveld Jeroen 
Published: August 2021

SUMMARYThe DNA damage response (DDR) is essential to maintain genome stability, and its deregulation predisposes to carcinogenesis while encompassing attractive targets for cancer therapy. Chromatin governs the DDR via the concerted interplay among different layers, including DNA, histone post-translational modifications (hPTMs), and chromatin-associated proteins. Here we employ multi-layered proteomics to characterize chromatin-mediated functional interactions of repair proteins, signatures of hPTMs, and the DNA-bound proteome during DNA double-strand break (DSB) repair at high temporal resolution. Our data illuminate the dynamics of known and novel DDR-associated factors both at chromatin and at DSBs. We functionally attribute novel chromatin-associated proteins to repair by non-homologous end-joining (NHEJ), homologous recombination (HR) and DSB repair pathway choice. We reveal histone reader ATAD2, microtubule organizer TPX2 and histone methyltransferase G9A as regulators of HR and PARP-inhibitor sensitivity. Furthermore, we distinguish hPTMs that are globally induced by DNA damage from those specifically acquired at sites flanking DSBs (γH2AX foci-specific), and profiled their dynamics during the DDR. Integration of complementary chromatin layers implicates G9A-mediated monomethylation of H3K56 at DSBs in HR. Our data provide a dynamic chromatin-centered view of the DDR that can be further mined to identify novel mechanistic links and cell vulnerabilities in DSB repair.
The role of genetic diversity and arbuscular mycorrhizal fungal diversity in population recovery of the semi-natural grassland plant species Succisa pratensis
Authors: Van Geel Maarten , Aavik Tsipe , Ceulemans Tobias , Träger Sabrina , Mergeay Joachim , Peeters Gerrit , van Acker Kasper , Zobel Martin , Koorem Kadri , Honnay Olivier 
Published: August 2021

AbstractBackgroundEcosystem restoration is as a critical tool to counteract the decline of biodiversity and recover vital ecosystem services. Restoration efforts, however, often fall short of meeting their goals. Although functionally important levels of biodiversity can significantly contribute to the outcome of ecosystem restoration, they are often overlooked. One such important facet of biodiversity is within-species genetic diversity, which is fundamental to population fitness and adaptation to environmental change. Also the diversity of arbuscular mycorrhizal fungi (AMF), obligate root symbionts that regulate nutrient and carbon cycles, potentially plays a vital role in mediating ecosystem restoration outcome. In this study, we investigated the relative contribution of intraspecific population genetic diversity, AMF diversity, and their interaction, to population recovery of Succisa pratensis, a key species of nutrient poor semi natural grasslands. We genotyped 180 individuals from 12 populations of S. pratensis and characterized AMF composition in their roots, using microsatellite markers and next generation amplicon sequencing, respectively. We also investigated whether the genetic makeup of the host plant species can structure the composition of root-inhabiting AMF communities.ResultsOur analysis revealed that population allelic richness was strongly positively correlated to relative population growth, whereas AMF richness and its interaction with population genetic diversity did not significantly contribute. The variation partitioning analysis showed that, after accounting for soil and spatial variables, the plant genetic makeup explained a small but significant part of the unique variation in AMF communities.ConclusionsOur results confirm that population genetic diversity can contribute to population recovery, highlighting the importance of within-species genetic diversity for the success of restoration. We could not find evidence, however, that population recovery benefits from the presence of more diverse AMF communities. Our analysis also showed that the genetic makeup of the host plant structured root-inhabiting AMF communities, suggesting that the plant genetic makeup may be linked to genes that control symbiosis development.
Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: August 2021

AbstractHeart failure (HF) is a complex cardiovascular diseases associated with high mortality. To discover key molecular changes in HF, we analyzed next-generation sequencing (NGS) data of HF. In this investigation, differentially expressed genes (DEGs) were analyzed using limma in R package from GSE161472 of the Gene Expression Omnibus (GEO). Then, gene enrichment analysis, protein-protein interaction (PPI) network, miRNA-hub gene regulatory network and TF-hub gene regulatory network construction, and topological analysis were performed on the DEGs by the Gene Ontology (GO), REACTOME pathway, STRING, HiPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, we performed receiver operating characteristic curve (ROC) analysis of hub genes. A total of 930 DEGs 9464 up regulated genes and 466 down regulated genes) were identified in HF. GO and REACTOME pathway enrichment results showed that DEGs mainly enriched in localization, small molecule metabolic process, SARS-CoV infections and the citric acid (TCA) cycle and respiratory electron transport. Subsequently, the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed, and 10 hub genes in these network were focused on by centrality analysis and module analysis. Furthermore, data showed that HSP90AA1, ARRB2, MYH9, HSP90AB1, FLNA, EGFR, PIK3R1, CUL4A, YEATS4 and KAT2B were good diagnostic values. In summary, this study suggests that HSP90AA1, ARRB2, MYH9, HSP90AB1, FLNA, EGFR, PIK3R1, CUL4A, YEATS4 and KAT2B may act as the key genes in HF.