bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Gold Standard for Transcription Factor Regulatory Interactions inEscherichia coliK-12: Architecture of Evidence Types
Authors: Lara Paloma , Gama-Castro Socorro , Salgado Heladia , Rioualen Claire , Tierrafría Víctor H. , Muñiz-Rascado Luis J. , Bonavides-Martínez César , Collado-Vides Julio 
Published: February 2023

AbstractPost-genomic implementations have expanded the experimental strategies to identify elements involved in the regulation of transcription initiation. As new methodologies emerge, a natural step is to compare their results with those from established methodologies, such as the classic methods of molecular biology used to characterize transcription factor binding sites, promoters, or transcription units.In the case ofEscherichia coliK-12, the best-studied microorganism, for the last 30 years we have continuously gathered such knowledge from original scientific publications, and have organized it in two databases, RegulonDB and EcoCyc. Furthermore, since RegulonDB version 11.0 (1), we offer comprehensive datasets of binding sites from chromatin immunoprecipitation combined with sequencing (ChIP-seq), ChIP combined with exonuclease digestion and next-generation sequencing (ChIP-exo), genomic SELEX screening (gSELEX), and DNA affinity purification sequencing (DAP-seq) HT technologies, as well as additional datasets for transcription start sites, transcription units and RNA sequencing (RNA-seq) expression profiles.Here, we present for the first time an analysis of the sources of knowledge supporting the collection of transcriptional regulatory interactions (RIs) ofE. coliK-12. An RI is formed by the transcription factor, its positive or negative effect on a promoter, a gene or transcription unit. We improved the evidence codes so that the specific methods are described, and we classified them into seven independent groups. This is the basis for our updated computation of confidence levels, weak, strong, or confirmed, for the collection of RIs. We compare the confidence levels of the RI collection before and after adding HT evidence illustrating how knowledge will change as more HT data and methods appear in the future. Users can generate subsets filtering out the method they want to benchmark and avoid circularity, or keep for instance only the confirmed interactions.The comparison of different HT methods with the available datasets indicate that ChIP-seq recovers the highest fraction (>70%) of binding sites present in RegulonDB followed by gSELEX, DAP-seq and ChIP-exo. There is no other genomic database that offers this comprehensive high-quality anatomy of evidence supporting a corpus of transcriptional regulatory interactions.
FOXP3+regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues
Authors: Martinez Hunter A. , Koliesnik Ievgen , Kaber Gernot , Reid Jacqueline K. , Nagy Nadine , Barlow Graham , Falk Ben A. , Medina Carlos O. , Hargil Aviv , Vlodavsky Israel , Li Jin-Ping , Pérez-Cruz Magdiel , Tang Sai-Wen , Meyer Everett H. , Wrenshall Lucile E. , Lord James D. , Garcia K. Christopher , Palmer Theo D. , Steinman Lawrence , Nepom Gerald T. , Wight Thomas N. , Bollyky Paul L. , Kuipers Hedwich F. 
Published: February 2023

AbstractFOXP3+regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resourcein vivo. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/-Treg have impaired stability and functionin vivo, including the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic functionin vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.One-Sentence SummaryRegulatory T cells use heparanase to strip IL-2 bound to extracellular matrix within inflamed tissues, thereby supporting their homeostasis and function.
Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses
Authors: Boys Ian N. , Johnson Alex G. , Quinlan Meghan , Kranzusch Philip J. , Elde Nels C. 
Published: February 2023

SummaryViruses acquire host genes via horizontal gene transfer and can express them to manipulate host biology during infections. Some viral and host homologs retain sequence identity, but evolutionary divergence can obscure host origins. We used structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identified vacciniaA47Las a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirmed this homology and cell-based assays revealed that A47 inhibits pyroptosis. We also identified vacciniaC1Las the product of a cryptic gene fusion event coupling a Bcl-2 related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting a benefit to poxvirus replication in some circumstances. Our findings demonstrate the potential of structural homology screens to reveal genes that viruses capture from hosts and repurpose to benefit viral fitness.
Whole-genome sequencing of ethnolinguistic diverse northwestern Chinese Hexi Corridor people from the 10K_CPGDP project suggested the differentiated East-West genetic admixture along the Silk Road and their biological adaptations
Authors: He Guanglin , Yao Hongbing , Sun Qiuxia , Duan Shuhan , Tang Renkuan , Chen Jing , Wang Zhiyong , Sun Yuntao , Li Xiangping , Wang Shaomei , Hu Liping , Yun Libing , Yang Junbao , Yan Jiangwei , Nie Shengjie , Zhu Yanfeng , Liu Chao , Wang Mengge 
Published: February 2023

AbstractThe ancient Silk Road served as the main connection between East and West Eurasia for several centuries. At any rate, the genetic exchange between populations along the ancient Silk Road was likely to leave traces on the contemporary gene pool of local people in Northwest China, which was the passage of the Northern Silk Road. However, genetic sources from northwestern China are under-represented in the current population-scale genomic database. To characterize the genetic architecture and adaptative history of the Northern Silk Road ethnic populations, we performed whole-genome sequencing on 126 individuals from six ethnolinguistic groups (Tibeto-Burman (TB)-speaking Tibetan, Mongolic (MG)-speaking Dongxiang/Tu/eastern Yugur, and Turkic (TK)-speaking Salar/western Yugur) living in Gansu and Qinghai in the 10K Chinese people Genomic Diversity Project (10K_CPGDP). We observed ethnicity-related differentiated population structures among these geographically close Northwest Chinese populations, that is, Salar and Tu people showed a close affinity with southwestern TB groups, and other studied populations shared more alleles with MG and Tungusic groups. Overall, the patterns of genetic clustering were not consistent with linguistic classifications. We estimated that Dongxiang, Tibetan, and Yugur people inherited more than 10% West Eurasian ancestry, much higher than that of Salar and Tu people (<7%). Hence, the difference in the proportion of West Eurasian ancestry has primarily contributed to the genetic divergence of geographically close Northwest Chinese populations. The signatures of natural selection were identified in genes associated with cardiovascular system diseases or lipid metabolism related to triglyceride levels (e.g.,PRIM2, PDE4DIP, NOTCH2, DDAH1, GALNT2, andMLIP) and developmental and neurogenetic diseases (e.g.,NBPFs 8/9/20/25P, etc.). Moreover, theEPAS1gene, a transcription factor regulating hypoxia response, showed relatively high PBS values in our studied groups. The sex-biased admixture history, in which the West Eurasian ancestry was introduced primarily by males, was identified in Dongxiang, Tibetan, and Yugur populations. We determined that the eastern-western admixture occurred ∼783–1131 years ago, coinciding with the intensive economic and cultural exchanges during the historic Trans-Eurasian cultural exchange era.
Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice
Authors: Togashi Tomoki , Baatartsogt Nemekhbayar , Nagao Yasumitsu , Kashiwakura Yuji , Hayakawa Morisada , Kamoshita Nobuhiko , Hiramoto Takafumi , Fujiwara Takayuki , Morishita Eriko , Nureki Osamu , Ohmori Tsukasa 
Published: February 2023

ABSTRACTProtein C (PC) is a plasma anticoagulant encoded byPROC; mutation in bothPROCalleles results in neonatal purpura fulminans—a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency. First, we generated an engineered activated PC to insert a self-cleaving peptide sequence between light and heavy chains. The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of protein Sin vitro. The adeno-associated virus (AAV) vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation factor V in a dose-dependent manner and abolished pathological thrombus formationin vivoin C57BL/6 mice. The insertion ofEGFPsequence conjugated with self-cleaving peptide sequence atAlblocus via neonatalin vivogenome editing using AAV vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editingin vivo. These results suggest that the expression of the engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.One Sentence SummaryEctopic expression of an engineered protein C via genome editing cures protein C deficiency in mice.
The IRE1α-endonuclease regulates PD-1 expression through a novel XBP1/miRNA-34a axis within Natural Killer cells
Authors: Bednarska Karolina , Thillaiyampalam Gayathri , Mujaj Sally , Nourse Jamie , Gunawardana Jay , Sabdia Muhammed B. , Cui Qingyan , de Long Lilia M. , Vari Frank , Gandhi Maher K. , Cristino Alexandre S. 
Published: February 2023

AbstractActivation of the IRE1α-endonuclease is critical for Natural Killer (NK)-cell function. We describe a novel regulatory role for IRE1α-endonuclease in fine-tuning NK-cell effector functions through an inter-connected activation of the transcription factor XBP1s and inhibition of microRNA-34a-5p (miR-34a-5p) to modulate PD-1 immune checkpoint expression. NK-cells, when exposed to cancer cells, activate IRE1α-endonuclease mediated decay of miR-34a-5p. This reduces miR-34a-5p and consequently increases the expression of the target genes XBP1 and PD-1. IRE1α-endonuclease activation not only enhances NK-cell effector function but also promotes PD-1 expression. PD-1 is itself directly regulated by miR-34a-5p, which binds to the 3’UTR of PD-1 messenger RNA to repress PD-1 protein at the NK-cell surface. IRE1α-pathway activation is impaired in the NK-cells of patients with Hodgkin Lymphoma, and miR-34a-5p and PD-1 expression are inversely correlated. The IRE1α-pathway plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK-cells, that is disrupted in cancer patients.
Immediate targeting of host ribosomes by jumbo phage encoded proteins
Authors: Gerovac Milan , Chihara Kotaro , Wicke Laura , Böttcher Bettina , Lavigne Rob , Vogel Jörg 
Published: February 2023

AbstractBacteriophages must seize control of the host gene expression machinery to promote their own protein synthesis. Since the bacterial hosts are armed with numerous anti-phage defence systems, it is essential that mechanisms of host take-over act immediately upon infection. Although individual proteins that modulate components of the bacterial gene expression apparatus have been described in several different phages, systematic approaches which capture the phage’s arsenal for immediate targeting of host transcription and translation processes have been lacking. In particular, there are no known phage factors that associate directly with host ribosomes to modulate protein synthesis. Here, we take an integrative high-throughput approach to uncover numerous new proteins encoded by the jumbo phage ΦKZ that target the gene expression machinery of the Gram-negative human pathogenPseudomonas aeruginosaimmediately upon infection. By integrating biochemical and structural analyses, we identify a conserved phage factor that associates with the large ribosomal subunit by binding the 5S ribosomal RNA. This highly abundant factor is amongst the earliest ΦKZ proteins expressed after infection and stays bound to ribosomes during the entire translation cycle. Our study provides a general strategy to decipher molecular components of phage-mediated host take-over and argues that phage genomes represent a large discovery space for proteins that modulate the host gene expression machinery.
Bacterial histone HBb fromBdellovibrio bacteriovoruscompacts DNA by bending
Authors: Hu Yimin , Schwab Samuel , Deiss Silvia , Escudeiro Pedro , van Heesch Thor , Joiner Joe D. , Vreede Jocelyne , Hartmann Marcus D. , Lupas Andrei N. , Alvarez Birte Hernandez , Alva Vikram , Dame Remus T. 
Published: February 2023

AbstractHistones are essential for genome compaction and transcription regulation in eukaryotes, where they assemble into octamers to form the nucleosome core. In contrast, archaeal histones assemble into dimers that form hypernucleosomes upon DNA binding. Although histone homologs have been identified in bacteria recently, their DNA-binding characteristics remain largely unexplored. Our study reveals that the bacterial histone HBb (Bd0055) is indispensable for the survival ofBdellovibrio bacteriovorus, suggesting critical roles in DNA organization and gene regulation. By determining crystal structures of free and DNA-bound HBb, we unveil its distinctive dimeric assembly, diverging from those of eukaryotic and archaeal histones, while also elucidating how it binds and bends DNA through interaction interfaces reminiscent of eukaryotic and archaeal histones. Building on this, by employing various biophysical and biochemical approaches, we further substantiated the ability of HBb to bind and compact DNA by bending in a sequence-independent manner. Finally, using DNA affinity purification and sequencing, we reveal that HBb binds along the entire genomic DNA ofB. bacteriovoruswithout sequence specificity. These distinct DNA-binding properties of bacterial histones, showcasing remarkable similarities yet significant differences from their archaeal and eukaryotic counterparts, highlight the diverse roles histones play in DNA organization across all domains of life.SummaryHistones, traditionally known for organizing and regulating DNA in eukaryotes and archaea, have recently been discovered in bacteria, opening up a new frontier in our understanding of genome organization across the domains of life. Our study investigates the largely unexplored DNA-binding properties of bacterial histones, focusing on HBb inBdellovibrio bacteriovorus. We reveal that HBb is essential for bacterial survival and exhibits DNA-binding properties similar to archaeal and eukaryotic histones. However, unlike eukaryotic and archaeal histones, which wrap DNA, HBb bends DNA without sequence specificity. This work not only broadens our understanding of DNA organization across different life forms but also suggests that bacterial histones may have diverse roles in genome organization.
Integrated analysis of gene expression and protein-protein interaction with tensor decomposition
Authors: Taguchi Y-H. , Turki Turki 
Published: February 2023

AbstractMotivationIntegration of gene expression (GE) and protein-protein interaction (PPI) is not straightforward because the former is provided as a matrix, whereas the latter is provided as a network. In many cases, genes processed with GE analysis are refined further based on a PPI network or vice versa. This is hardly regarded as a true integration of GE and PPI. To address this problem, we proposed a tensor decomposition (TD) based method that can integrate GE and PPI prior to any analyses where PPI is also formatted as a matrix to which singular value decomposition (SVD) is applied.ResultsIntegrated analyses with TD improved the coincidence between vectors attributed to samples and class labels over 27 cancer types retrieved from The Cancer Genome Atlas Program (TCGA) toward five class labels. Enrichment using genes selected with this strategy were also improved with the integration using TD. The PPI network associated with the information on the strength of the PPI can improve the performance than PPI that stores only if the interaction exists in individual pairs. In addition, even restricting genes to the intersection of GE and PPI can improve coincidence and enrichment.Availability and implementationThe R source code used to perform this analyses is in the supplementary file.
Mobile brain imaging in butoh dancers: from rehearsals to public performance
Authors: Theofanopoulou Constantina , Paez Sadye , Huber Derek , Todd Eric , Ramírez-Moreno Mauricio A. , Khaleghian Badie , Sánchez Alberto Muñoz , Barceló Leah , Gand Vangeline , Contreras-Vidal José L. 
Published: February 2023

AbstractDissecting the neurobiology of dance would shed light on a complex, yet ubiquitous, form of human communication. In this experiment, we sought to study, via mobile electroencephalography (EEG), the brain activity of five experienced dancers while dancing butoh, a postmodern dance that originated in Japan. We report the experimental design, methods, and practical execution of a highly interdisciplinary project that required the collaboration of dancers, engineers, neuroscientists, musicians, and multimedia artists, among others. We explain in detail how we technically validated all our EEG procedures (e.g., via impedance value monitoring) and how we minimized potential artifacts in our recordings (e.g., via electrooculography and inertial measurement units). We also describe the engineering details and hardware that enabled us to achieve synchronization between signals recorded in different sampling frequencies, and a signal preprocessing and denoising pipeline that we have used to re-sample our data and remove power line noise. As our experiment culminated in a live performance, where we generated a real-time visualization of the dancers’ interbrain synchrony on a screen via an artistic brain-computer interface, we outline all the methodology (e.g., filtering, time-windows, equation) we used for online bispectrum estimations. We also share all the raw EEG data and codes we used in our recordings. We, lastly, describe how we envision that the data could be used to address several hypotheses, such as that of interbrain synchrony or the motor theory of vocal learning. Being, to our knowledge, the first study to report synchronous and simultaneous recording from five dancers, we expect that our findings will inform future art-science collaborations, as well as dance-movement therapies.
A generalizable Cas9/sgRNA prediction model using machine transfer learning with small high-quality datasets
Authors: Ham Dalton T. , Browne Tyler S. , Banglorewala Pooja N. , Wilson Tyler , Michael Richard , Gloor Gregory B. , Edgell David R. 
Published: February 2023

ABSTRACTThe CRISPR/Cas9 nuclease fromStreptococcus pyogenes(SpCas9) can be used with single guide RNAs (sgRNAs) as a sequence-specific antimicrobial agent and as a genome-engineering tool. However, current bacterial sgRNA activity models poorly predict SpCas9/sgRNA activity and are not generalizable, possibly because the underlying datasets used to train the models do not accurately measure SpCas9/sgRNA cleavage activity and cannot distinguish cleavage activity from toxicity. We solved this problem by using a two-plasmid positive selection system to generate high-quality biologically-relevant data that more accurately reports on SpCas9/sgRNA cleavage activity and that separates activity from toxicity. We developed a new machine transfer learning architecture (crisprHAL) that can be trained on existing datasets and that shows marked improvements in sgRNA activity prediction accuracy when transfer learning is used with small amounts of high-quality data. The crisprHAL model recapitulates known SpCas9/sgRNA-target DNA interactions and provides a pathway to a generalizable sgRNA bacterial activity prediction tool.
Mass spectrometric profiling of HLA-B44 peptidomes provides evidence for tapasin-mediated tryptophan editing
Authors: Kaur Amanpreet , Surnilla Avrokin , Zaitouna Anita J. , Basrur Venkatesha , Mumphrey Michael B. , Grigorova Irina , Cieslik Marcin , Carrington Mary , Nesvizhskii Alexey I. , Raghavan Malini 
Published: February 2023

AbstractActivation of CD8+T cells against pathogens and cancers involves the recognition of antigenic peptides bound to human leukocyte antigen (HLA) class-I proteins. Peptide binding to HLA class I proteins is coordinated by a multi-protein complex called the peptide loading complex (PLC). Tapasin, a key PLC component, facilitates the binding and optimization of HLA class I peptides. However, different HLA class I allotypes have variable requirements for tapasin for their assembly and surface expression. HLA-B*44:02 and HLA-B*44:05, which differ only at residue 116 of their heavy chain sequences, fall at opposite ends of the tapasin-dependency spectrum. HLA-B*44:02 (D116) is highly tapasin-dependent, whereas HLA-B*44:05 (Y116) is highly tapasinindependent. Mass spectrometric comparisons of HLA-B*4405 and HLA-B*44:02 peptidomes were undertaken to better understand the influences of tapasin upon HLA-B44 peptidome compositions. Analyses of the HLA-B*44:05 peptidomes in the presence and absence of tapasin reveal that peptides with the C-terminal tryptophan residues and those with higher predicted binding affinities are selected in the presence of tapasin. Additionally, when tapasin is present, C-terminal tryptophans are also more highly represented among peptides unique to B*44:02 and those shared between B*44:02 and B*44:05, compared with peptides unique to B*44:05. Overall, our findings demonstrate that tapasin influences the C-terminal composition of HLA class I-bound peptides and favors the binding of higher affinity peptides. For the HLA-B44 family, the presence of tapasin or high tapasin-dependence of an allotype results in better binding of peptides with C-terminal tryptophans, consistent with a role for tapasin in stabilizing an open conformation to accommodate bulky C-terminal residues.