bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silicoanalysis ofcis-elements and identification of transcription factors putatively involved in the regulation of the OAS cluster genesSDI1andSDI2
Authors: Rakpenthai Apidet , Apodiakou Anastasia , Whitcomb Sarah J. , Hoefgen Rainer 
Published: April 2021

SUMMARYA. thaliana sulfur deficiency-induced 1andsulfur deficiency-induced 2(SDI1andSDI2) are involved in partitioning sulfur among metabolite pools during sulfur deficiency and their transcription is strongly induced by this condition. However, little is currently known about thecis- andtrans-factors that regulateSDIexpression. To identify potential transcription factors and DNA sequence element regulators ofSDIexpression we performed a comparativein silicoanalysis of their promoter sequences cataloguing known and potentially newcis-elements. We further screened an arrayed library of Arabidopsis transcription factors (TF) for binding to theSDI1andSDI2promoters. In total 14 candidate TF regulators ofSDIs were identified with yeast-one-hybrid analyses, of which five bound to both promoters, 4 were specific toSDI1,and 5 were specificSDI2. Direct association between particularcis-elements in these promoter regions and specific TFs was established via electrophoretic mobility shift assays. SLIM1 was shown to bind SUREcis-element(s) in the proximal promoter region of bothSDI1andSDI2. The bZIP corecis-element in the proximal promoter region ofSDI2was shown to be important for bZIP16, bZIP44, and HYH binding. GBF1 was shown to bind the E-box in the proximal promoter region ofSDI2. Additionally, we performed a meta-analysis of expression changes of these 14 TF candidates in a variety of conditions that alterSDIexpression. These data will allow for more detailed future analysis of the molecular factors required for transcriptional regulation ofSDIs under a range of physiological and metabolic conditions, apart from sulfur deficiency.
The effect of double biofeedback on functional hemispheric asymmetry and activity: a pilot study
Authors: Demareva Valeriia , Mukhina Elena , Bobro Tatiana 
Published: April 2021

AbstractIn the current pilot study, we attempt to find out how double neurofeedback influences functional hemispheric asymmetry and activity. We examined 30 healthy participants (8 males; 22 females, mean age = 29; SD= 8). To measure functional hemispheric asymmetry and activity, we used computer laterometry in the ‘two-source’ lead-lag dichotic paradigm. Double biofeedback included 8 minutes of EEG oscillation recording with five minutes of basic mode. During the basic mode, the current amplitude of the EEG oscillator gets transformed into feedback sounds while the current amplitude of alpha EEG oscillator is used to modulate the intensity of light signals. Double neurofeedback did not directly influence the asymmetry itself but accelerated individual sound perception characteristics during dichotic listening in the preceding effect paradigm. Further research is needed to investigate the effect of double neurofeedback training on functional brain activity and asymmetry taking into account participants’ age, gender, and motivation.
ADAPTATION OF DOLPHINS (TURSIOPS TRUNCATUS) LOCATION SIGNALS WHEN SEARCHING AND RECOGNIZING OBJECTS HIDDEN BY SEA SEDIMENTS
Authors: Zaitseva K. A. , Korolev V. I. , Akhi A. V. , Akhi A. A. 
Published: April 2021

ABSTRACTAn experimental study was conducted to research dolphin’s sonar adaptation capabilities for location of objects obscured by marine sediments. It was shown that dolphins are able to alter spectral and temporal characteristics of their location signals. Adaptive change of length, spectral width, and amplitude of impulses provides optimal tools to fight interference and allows dolphins to effectively identify objects.SUMMARYThis work describes dolphin’s search, location and recognition objects hidden by sea sediments and changes in its location signal structure.
Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles
Authors: Jones Ross D. , Qian Yili , Ilia Katherine , Wang Benjamin , Laub Michael T. , Del Vecchio Domitilla , Weiss Ron 
Published: April 2021

AbstractRewired and synthetic signaling networks can impart cells with new functionalities and enable efforts in engineering cell therapies and directing cell development. However, there is a need for tools to build synthetic signaling networks that are tunable, can precisely regulate target gene expression, and are robust to perturbations within the complex context of mammalian cells. Here, we use proteins derived from bacterial two-component signaling pathways to develop synthetic phosphorylation-based and feedback-controlled devices in mammalian cells with such properties. First, we isolate kinase and phosphatase proteins from the bifunctional histidine kinase EnvZ. We then use these proteins to engineer a synthetic covalent modification cycle, in which the kinase and phosphatase competitively regulate phosphorylation of the cognate response regulator OmpR, enabling analog tuning of OmpR-driven gene expression. Further, we show that the phosphorylation cycle can be extended by connecting phosphatase expression to small molecule and miRNA inputs in the cell, with the latter enabling cell-type specific signaling responses and accurate cell type classification. Finally, we implement a tunable negative feedback controller by co-expressing the kinase-driven output gene with the small molecule-tunable phosphatase. This negative feedback substantially reduces cell-to-cell noise in output expression and mitigates the effects of cell context perturbations due to off-target regulation and resource competition. Our work thus lays the foundation for establishing tunable, precise, and robust control over cell behavior with synthetic signaling networks.
Multi-omics approach to identify bacterial polyynes and unveil their antifungal mechanism against Candida albicans
Authors: Lin Ching-Chih , Hoo Sin Yong , Lin Chih , Huang Kai-Fa , Ho Ying-Ning , Sun Chi-Hui , Lee Han-Jung , Chen Pi-Yu , Shu Lin-Jie , Wang Bo-Wei , Hsu Wei-Chen , Yang Yu-Liang 
Published: April 2021

AbstractBacterial polyynes are highly active natural products with a broad-spectrum of antimicrobial activities. However, their detailed mechanism of action remains unclear. Through integrating comparative genomics, transcriptomics, functional genetics, and metabolomics analysis, we identified a unique polyyne resistance gene, masL (encoding acetyl-CoA acetyltransferase), from the biosynthesis gene cluster (BGC) dominant for the production of antifungal polyynes (massilin A, massilin B, collimonin C, and collimonin D) in Massilia sp. YMA4. Phylogenic and chemotaxonomic analyses characterized the core architecture of bacterial polyyne BGC. The crystallographic analysis of the MasL-collimonin C complex indicated that bacterial polyynes serve as a covalent inhibitor of acetyl-CoA acetyltransferase. Moreover, we confirmed that the bacterial polyynes disrupted cell membrane integrity and inhibited cell viability of Candida albicans by targeting ERG10 (homolog of MasL). Overall, understanding of the antifungal mechanism of bacterial polyynes presented herein will be useful for the development of polyynes for fungal infections.
An MHV macrodomain mutant predicted to lack ADP-ribose binding activity is severely attenuated, indicating multiple roles for the macrodomain in coronavirus replication
Authors: Voth Lynden S. , O’Connor Joseph J. , Kerr Catherine M. , Doerger Ethan , Schwarting Nancy , Sperstad Parker , Johnson David K. , Fehr Anthony R. 
Published: April 2021

ABSTRACTAll coronaviruses (CoVs) contain a macrodomain, also termed Mac1, in non-structural protein 3 (nsp3) which binds and hydrolyzes ADP-ribose covalently attached to proteins. Despite several reports demonstrating that Mac1 is a prominent virulence factor, there is still a limited understanding of its cellular roles during infection. Currently, most of the information regarding the role of CoV Mac1 during infection is based on a single point mutant of a highly conserved asparagine-to-alanine mutation, which is known to largely eliminate Mac1 ADP-ribosylhydrolase activity. To determine if Mac1 ADP-ribose binding separately contributes to CoV replication, we compared the replication of a murine hepatitis virus (MHV) Mac1 mutant predicted to dramatically reduce ADP-ribose binding, D1329A, to the previously mentioned asparagine mutant, N1347A. D1329A and N1347A both replicated poorly in bone-marrow derived macrophages (BMDMs), were inhibited by PARP enzymes, and were highly attenuatedin vivo. However, D1329A was significantly more attenuated than N1347A in all cell lines tested that were susceptible to MHV infection. In addition, D1329A retained some ability to block IFN-β transcript accumulation compared to N1347A, indicating that these two mutants impacted distinct Mac1 functions. Mac1 mutants predicted to eliminate both binding and hydrolysis activities were unrecoverable, suggesting that the combined activities of Mac1 may be essential for MHV replication. We conclude that Mac1 has multiple roles in promoting the replication of MHV, and that these results provide further evidence that Mac1 could be a prominent target for anti-CoV therapeutics.IMPORTANCEIn the wake of the COVID-19 epidemic, there has been a surge to better understand how CoVs replicate, and to identify potential therapeutic targets that could mitigate disease caused by SARS-CoV-2 and other prominent CoVs. The highly conserved macrodomain, also termed Mac1, is a small domain within non-structural protein 3. It has received significant attention as a potential drug target as previous studies demonstrated that it is essential for CoV pathogenesis in multiple animal models of infection. However, the various roles and functions of Mac1 during infection remain largely unknown. Here, utilizing recombinant Mac1 mutant viruses, we have determined that different biochemical functions of Mac1 have distinct roles in the replication of MHV, a model CoV. These results indicate that Mac1 is more important for CoV replication than previously appreciated, and could help guide the development of inhibitory compounds that target unique regions of this protein domain.
Genomic Analysis of Human Noroviruses Using Hybrid Illumina-Nanopore Data
Authors: Flint Annika , Reaume Spencer , Harlow Jennifer , Hoover Emily , Weedmark Kelly , Nasheri Neda 
Published: April 2021

AbstractWhole genome sequence (WGS) analysis of noroviruses is routinely performed by employing a metagenomic approach. While this methodology has several advantages, such as allowing for examination of co-infection, it has some limitations such as the requirement of high viral load to achieve full-length or near full-length genomic sequences. In this study, we used an amplification approach to obtain full-length genomic amplicons from 39 Canadian GII isolates followed by deep sequencing on Illumina and Oxford Nanopore platforms. This approach significantly reduced the required viral titre to obtain full-genome coverage. Herein, we compared the coverage and sequences obtained by both platforms and provided an in-depth genomic analysis of the obtained sequences, including the presence of single nucleotide variants (SNVs) and recombination events.
Mechanisms involved in the active secretion of CTX-M-15 β-lactamase by pathogenicE. coliST131
Authors: Rangama Severine , Lidbury Ian D. E. A , Holden Jennifer M. , Borsetto Chiara , Murphy Andrew R. J. , Hawkey Peter M. , Wellington Elizabeth M. H. 
Published: April 2021

AbstractInfections caused by antimicrobial resistant bacterial pathogens are fast becoming an important global health issue. Strains ofEscherichia coliare common causal agents of urinary tract infection and can carry multiple resistance genes. This includes the geneblaCTX-M-15that encodes for an extended spectrum beta-lactamase (ESBL). While studying antimicrobial resistance (AMR) in the environment we isolated several strains ofE. coliST131 downstream of a WWTP in a local river. These isolates were surviving in the river sediment and characterisation proved that a multi-resistant phenotype was evident. Here, we show thatE. colistrain 48 (river isolate ST131), provided a protective effect against a third-generation cephalosporin (cefotaxime) for a susceptibleE. colistrain 33 (river isolate ST3576) through secretion of a functional ESBL into the growth medium. Furthermore, extracellular ESBL activity was stable for at least 24 h after secretion. Proteomic and molecular genetic analyses identified CTX-M-15 as the major secreted ESBL responsible for the observed protective effect. In contrast to previous studies, OMVs were not the sole route for CTX-M-15 secretion. Indeed, mutation of the Type I secretion system led to a significant reduction in the growth of the ESBL-producing strain as well as a significantly reduced ability to confer protective effect. We speculate that CTX-M-15 secretion, mediated through active secretion using molecular machinery provides a public goods service by facilitating the survival of otherwise susceptible bacteria in the presence of cefotaxime.Abstract importanceInfections caused by antimicrobial resistant bacterial pathogens have become an important global health issue. Wastewater treatment plants (WWTPs) have been identified as hotspots for the dissemination of antimicrobial resistant genes/bacteria into the environment. In this study, we investigated resistance enzyme secretion by a multi-drug resistant human pathogenicE. coli, isolated from a UK river, downstream of a WWTP. We present evidence that the resistant strain actively secreted an important resistance enzyme into the surrounding medium which degraded the antibiotic cefotaxime. This research provided evidence for the mechanism for secretion of this enzyme which could indicate a new target to tackle antibiotic resistance pathogens.
Linking Diabetes mellitus to SARS-CoV-2 infection through differential targeting of the microRNAs in the Pancreas tissue
Authors: Bhavya  , Pathak Ekta , Mishra Rajeev 
Published: April 2021

AbstractCoronavirus Disease 2019 (COVID-19) severity and Diabetes mellitus affect each other bidirectionally. The plus-sense single-stranded RNA (+ssRNA) genome of the SARS-CoV-2 virus can be targeted and suppressed by the host cell’s microRNAs (miRNAs). Using the differential gene expression analysis between the mock-infected and the SARS-CoV-2-infected pancreatic tissue, we report five Diabetes-associated genes that are upregulated due to SARS-CoV-2 infection in the hESC pancreas tissues. Ten miRNAs regulating these five genes can potentially target the SARS-CoV-2 genome. We hypothesize that the SARS-CoV-2 genome copies in the infected human pancreas cell compete with the host cell’s native genes in being regulated by the native miRNAs. It leads to the reduced miRNA-regulation and, thus, the upregulation of the Diabetes-associated native genes. Thus, the resultant new-onset or elevated Diabetic symptoms may worsen the condition of COVID-19 patients.
A tyrosine-based trafficking signal in the simian immunodeficiency virus envelope cytoplasmic domain is strongly selected for in pathogenic SIV infection
Authors: Lawrence Scott P. , Elser Samra E. , Torben Workineh , Blair Robert V. , Pahar Bapi , Aye Pyone P. , Schiro Faith , Szeltner Dawn , Doyle-Meyers Lara A. , Haggarty Beth , Jordan Andrea P.O. , Romano Josephine , Alvarez Xavier , O’Connor David H. , Wiseman Roger W. , Fennessey Christine M. , Li Yuan , Piatak Michael , Lifson Jeffrey D. , LaBranche Celia C. , Lackner Andrew A. , Keele Brandon F. , Maness Nicholas J. , Marsh Mark , Hoxie James A. 
Published: April 2021

SUMMARYThe HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-dependent trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting of Env. Despite extensive characterization, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which the Tyr-based signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY) replicates to high levels acutely in pigtail macaques (PTM) but is rapidly controlled. We previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion that encodes amino acids 734-736 (ΔQTH) and overlaps with therevandtatopen reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected, which generated a new signal for polarized sorting but not endocytosis. This mutation by itself was sufficient to maintain high viral loads for several months when introduced into naïve PTMs. These findings reveal, for the first time, strong selection pressure for Env endocytosis and, in particular, for polarized sorting during pathogenic SIV infectionin vivo.
Suppression ofcdc13-2-associated senescence bypif1-m2requires Ku-mediated telomerase recruitment
Authors: Fekete-Szücs Enikő , Rosas Bringas Fernando R. , Stinus Sonia , Chang Michael 
Published: April 2021

AbstractInSaccharomyces cerevisiae, recruitment of telomerase to telomeres requires an interaction between Cdc13, which binds single-stranded telomeric DNA, and the Est1 subunit of telomerase. A second pathway involving an interaction between the yKu complex and telomerase RNA (TLC1) contributes to telomerase recruitment, but cannot sufficiently recruit telomerase on its own to prevent replicative senescence when the primary Cdc13-Est1 pathway is abolished—for example, in thecdc13-2mutant. In this study, we find that mutation ofPIF1, which encodes a helicase that inhibits telomerase, suppresses the replicative senescence ofcdc13-2increasing reliance on the yKu-TLC1 pathway for telomerase recruitment. Our findings reveal new insight into telomerase-mediated telomere maintenance.
JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2
Authors: Kim Eun-Jung , Kim Jung Yun , Kim Sung-Ok , Ham Seok Won , Choi Sang-Hun , Hong Nayoung , Park Min Gi , Jang Junseok , Seo Sunyoung , Lee Kanghun , Jeong Hyeon Ju , Kim Sung Jin , Jeong Sohee , Min Kyungim , Kim Sung-Chan , Jin Xiong , Kim Se Hoon , Kim Sung-Hak , Kim Hyunggee 
Published: April 2021

AbstractJagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.
Liquid-to-solid phase transition ofoskarRNP granules is essential for their function in theDrosophilagermline
Authors: Bose Mainak , Mahamid Julia , Ephrussi Anne 
Published: April 2021

SummaryAsymmetric localization ofoskarRNP granules to the oocyte posterior is crucial for abdominal patterning and germline formation of theDrosophilaembryo. We show thatoskarRNP granules in the oocyte are condensates with solid-like physical properties. Using purifiedoskarRNA and scaffold proteins Bruno and Hrp48, we confirmin vitrothatoskargranules undergo a liquid-to-solid phase transition. Whereas the liquid phase allows RNA incorporation, the solid phase precludes incorporation of additional RNA while allowing RNA-dependent partitioning of specific proteins. Genetic modification of scaffold granule proteins, or tethering the intrinsically disordered region of human Fused in Sarcoma tooskarmRNA, allowed modulation of granule material propertiesin vivo. The resulting liquid-like properties impairedoskarlocalization and translation with severe consequences on embryonic development. Our study reflects how physiological phase transitions shape RNA-protein condensates to regulate localization and expression of a maternal RNA that instructs germline formation.
The effect of histone deacetylase inhibitor Trichostatin A on IL-17A-induced transformation of MRC5 into myofibroblasts and its mechanism
Authors: Zhang Qian , Guo Zexin , Zhang Jing , Zhou Wei , Wu Yueqing , Dong Lixia , Feng Jing , Li Shuo , Cao Jie 
Published: April 2021

AbstractObjectiveTo elucidate potential IL-17A- and TSA-mediated regulation of fibroblasts transformation.MethodsMTT assay, HDAC1 activity assay, cell immunofluorescence and Western blot were employed to detect the expression of related indicators.ResultsMRC5 cells expressed only a small amount of Vimentin. IL-17A treatment upregulated MRC5 cell proliferation, in a concentration-dependent manner. TSA treatment, however, suppressed MRC5 cell proliferation. IL-17A treatment also upregulated HDAC1 activity in MRC5 cells, in a concentration-dependent manner. Using immunofluorescence, we demonstrated that IL-17A-treated MRC5 cells had markedly elevated Vimentin, Collagen-I and a-SMA levels, compared to controls. However, a combined treatment of IL-17A and TSA resulted in markedly reduced levels of the Vimentin, Collagen-I and a-SMA, compared to IL-17A alone, yet the amount was higher than controls. Using western blot analysis, we also revealed that the IL-17A-treated MRC5 cells had markedly elevated levels of Vimentin, a-SMA, HDAC1, p-Smad2, and p-Smad3, and markedly reduced level of Smad7, compared to controls. In TSA intervention group, the expression effect of the above protein was opposite. Moreover, no discernible difference was observed in the levels of Smad2 and Smad3 among the treated and un-treated groups.ConclusionIL-17A stimulates proliferation of MRC5 cells and increases HDAC1 activity and protein expression. It also transforms MRC5 cells into myofibroblasts via activation of the TGF -β1/ Smads signaling network. TSA, on the other hand, strongly suppresses TGF -β1/ Smads pathway-mediated fibrosis by ceasing HDAC1 activity and protein expression.