bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
Authors: Yang Chunsong , Wierbiłowicz Krzysztof , Dworak Natalia M , Bae Song Yi , Tengse Sachi B. , Abianeh Nicki , Drake Justin M. , Abbas Tarek , Ratan Aakrosh , Wotton David , Paschal Bryce M 
Published: September 2022

ABSTRACTThe ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergentresistant fraction within the nucleus, which is reminiscent of how inhibitors such as Talazoparib affect PARP1 fractionation. Because PARP7 is expressed in AR negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.SignificanceRBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically-used PARP1 inhibitors.
Quantifying and Visualizing Uncertainty for Source Localization in Electrocardiographic Imaging
Authors: Njeru Dennis K. , Athawale Tushar M. , France Jessie J. , Johnson Chris R. 
Published: September 2022

ABSTRACTElectrocardiographic imaging (ECGI) presents a clinical opportunity to noninvasively understand the sources of arrhythmias for individual patients. To help increase the effectiveness of ECGI, we provide new ways to visualize associated measurement and modeling errors. In this paper, we study source localization uncertainty in two steps: First, we perform Monte Carlo simulations of a simple inverse ECGI source localization model with error sampling to understand the variations in ECGI solutions. Second, we present multiple visualization techniques, including confidence maps, level-sets, and topology-based visualizations, to better understand uncertainty in source localization. Our approach offers a new way to study uncertainty in the ECGI pipeline.
Slow and not so furious: de novo stomatal pattern formation during plant embryogenesis
Authors: Smit Margot E , Vatén Anne , Mair Andrea , Northover Carrie A M , Bergmann Dominique C 
Published: September 2022

AbstractThe fates of cells on the leaf surface depend on positional cues and environmental signals. New stomata are formed away from existing ones to prevent disadvantageous clustering, but how are the initial precursors positioned? Mature embryos do not have stomata, but we provide transcriptomic, imaging, and genetic evidence that Arabidopsis embryos engage known stomatal fate and patterning factors to create regularly spaced stomatal precursor cells. Analysis of embryos from 35 plant species indicates this trait is conserved across angiosperm clades. Embryonic stomatal patterning in Arabidopsis is established in three stages: first broad SPEECHLESS (SPCH) expression, then coalescence of SPCH and its targets into discrete domains, and finally one round of symmetric division to create stomatal precursors. Lineage progression is then halted until after germination. We show that embryonic stomatal pattern enables quick stomatal differentiation and photosynthetic activity upon germination but also guides the formation of additional stomata as the leaf expands. In addition, key stomatal regulators are prevented from driving the fate transitions they can induce after germination, revealing stage-specific layers of regulation that control lineage progression during embryogenesis.
Dynamic regulation of gonadal transposon control across the lifespan of the naturally short-lived African turquoise killifish
Authors: Teefy Bryan B. , Adler Ari , Xu Alan , Hsu Katelyn , Singh Param Priya , Benayoun Bérénice A. 
Published: September 2022

AbstractAlthough germline cells are considered to be functionally “immortal”, both the germline and supporting somatic cells in the gonad within an organism will experience aging. With increased age at parenthood, the age-related decline in reproductive success has become an important biological issue for an aging population. However, molecular mechanisms underlying reproductive aging across sexes in vertebrates remain poorly understood. To decipher molecular drivers of vertebrate gonadal aging across sexes, we perform longitudinal characterization of the gonadal transcriptome throughout lifespan in the naturally short-lived African turquoise killifish(Nothobranchius furzeri). By combining mRNA-seq and small RNA-seq from 26 individuals, we characterize the aging gonads of young adult, middle-aged, and old female and male fish. We analyze changes in transcriptional patterns of genes, transposable elements (TEs), and piRNAs. We find that testes seem to undergo only marginal changes during aging. In contrast, in middle-aged ovaries, the timepoint associated with peak female fertility in this strain, PIWI pathway components are transiently downregulated, TE transcription is elevated, and piRNA levels generally decrease, suggesting that egg quality may already be declining at middle-age. Furthermore, we show that piRNA ping-pong biogenesis declines steadily with age in ovaries, while it is maintained in aging testes. To our knowledge, this dataset represents the most comprehensive transcriptomic dataset for vertebrate gonadal aging. This resource also highlights important pathways that are regulated during reproductive aging in either ovaries or testes, which could ultimately be leveraged to help restore aspects of youthful reproductive function.
G-quadruplex landscape and its regulation revealed by a new antibody capture method
Authors: Datta Subhamoy , Patel Manthan , Sathyaseelan Chakkarai , Ghosh Chandrama , Mudgal Akanksha , Patel Divyesh , Rathinavelan Thenmalarchelvi , Singh Umashankar 
Published: September 2022

ABSTRACTOur understanding of DNA G-quadruplexes (G4s) fromin vitrostudies has been complemented by genome-wide G4 landscapes from cultured cells. Conventionally, the formation of G4s is accepted to depend on G-repeats such that they form tetrads. However, genome-wide G4s characterized through high-throughput sequencing suggest that these structures form at a large number of regions with no such canonical G4-forming signatures. Many G4-binding proteins have been described with no evidence for any protein that binds to and stabilizes G4s. It remains unknown what fraction of G4s formed in human cells are protein-bound. The G4-chromatin immunoprecipitation (G4-ChIP) method hitherto employed to describe G4 landscapes preferentially reports G4s that get crosslinked to proteins in their proximity. Our current understanding of the G4 landscape is biased against representation of G4s which escape crosslinking as they are not stabilized by protein-binding and presumably transient. We report a protocol that captures G4s from the cells efficiently without any bias as well as eliminates the detection of G4s formed artifactually on crosslinked sheared chromatin post-fixation. We discover that G4s form sparingly at SINEs. An application of this method shows that depletion of a repeat-binding protein CGGBP1 enhances net G4 capture at CGGBP1-dependent CTCF-binding sites and regions of sharp interstrand G/C-skew transitions. Thus, we present an improved method for G4 landscape determination and by applying it we show that sequence property-specific constraints of the nuclear environment mitigate G4 formation.
DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing N6-methyladenosine binding
Authors: Li Mengyao , Li Jie , Yuan Aiyun , Dong Weidong , Dong Suwei , Yang Yun-Gui , Wang Yibo , Wu Chen , Li Jing 
Published: September 2022

AbstractN6-methyladenosine (m6A) is the most prevalent RNA modification, and its regulators include writers, readers and erasers. m6A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m6A and glycosylation. Here we investigated an m6A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced foci (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m6A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m6A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR and genome stability.
Delayed SARS-CoV-2 Spread and Olfactory Cell Lineage Impairment in Close-Contact Infection Syrian Hamster Models
Authors: Ueha Rumi , Ito Toshihiro , Ueha Satoshi , Furukawa Ryutaro , Kitabatake Masahiro , Ouji-Sageshima Noriko , Uranaka Tsukasa , Tanaka Hirotaka , Nishijima Hironobu , Kondo Kenji , Yamasoba Tatsuya 
Published: September 2022

AbstractObjectivesClose contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2.MethodsSyrian hamsters were orally administered SARS-CoV-2 as direct-infection models. On day 7 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs, were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups.ResultsIn the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p < 0.001) and showed a recovery trend on day 14, with similar trends for olfactory progenitors and immature ORNs. In the close-contact group, there was no obvious tissue damage on day 3, but on day 7, the number of all ORN lineage cells significantly decreased (p < 0.001).ConclusionSARS-CoV-2 was transmitted even after brief contact and subsequent olfactory epithelium and lung damage occurred more than 3 days after the trigger of infection. The present study also indicated that SARS-CoV-2 damages all ORN lineage cells, but this damage can begin to recover approximately 14 days post infection.
Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response
Authors: Arora Rohit , Cao Christian , Kumar Mehul , Sinha Sarthak , Chanda Ayan , McNeil Reid , Samuel Divya , Arora Rahul K. , Matthew T. Wayne , Chandarana Shamir , Hart Robert , Dort Joseph C. , Biernaskie Jeff , Neri Paola , Hyrcza Martin D. , Bose Pinaki 
Published: September 2022

AbstractWe performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biologies, a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) and is foundational for developing novel targeted therapies.
ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2
Authors: Chen Feng , Chen Yanting , Ke Qiongwei , Wang Yongxiang , Chen Xiongjin , Peng Xiaoping , Cai Yujie , Li Shennan , Sun Yuanhong , Ji Yao , Jiang Yuling , Wu Wenxian , Wang Yan , Cui Lili 
Published: September 2022

AbstractThe coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); host cell entry by this virus relies on the interaction between the receptor-binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor on cell membranes. In addition to serving as a receptor for SARS-CoV-2, ACE2 was originally discovered as a protective factor in the renin–angiotensin system (RAS) that catalyses the degradation of angiotensin II (Ang II) to Ang 1-7, which is involved in multiple organ pathology. Recent genetic and clinical studies reported that ApoE4 expression is associated with increased susceptibility to SARS-CoV-2 infection and the development of severe COVID-19, but the underlying mechanism is currently unclear. In the present study, by using immunofluorescence staining, molecular dynamics simulations, proximity ligation assay (PLA) and coimmunoprecipitation (Co-IP) combined with a biolayer interferometry (BLI) assay, we found that ApoE interacts with both the spike protein and ACE2 but does not show obvious isoform-dependent binding effects. These data suggest that ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Importantly, further immunoblotting and immunofluorescence staining results showed that ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7, which could worsen tissue lesions; these findings provide a possible explain by which ApoE4 exacerbates COVID-19 disease.
Structure-based prediction of Ras-effector binding affinities and design of ‘branchegetic’ interface mutations
Authors: Junk Philipp , Kiel Christina 
Published: September 2022

SummaryRas is a central cellular hub protein controlling multiple cell fates. How Ras interacts with a variety of potential effector proteins is relatively unexplored, with only some key effectors characterized in great detail. Here, we have used homology modelling based on X-ray and AlphaFold2 templates to build structural models for 54 Ras-effectors complexes. These models were used to estimate binding affinities using a supervised learning regressor. Furthermore, we systematically introduced Ras ‘branch-pruning’ (or branchegetic) mutations to identify 200 interface mutations that affect the binding energy with at least one of the model structures. The impacts of these branchegetic mutants were integrated into a mathematical model to assess the potential for rewiring interactions at the Ras hub on a systems level. These findings have provided a quantitative understanding of Ras-effector interfaces and their impact on systems properties of a key cellular hub.
Whole-genome duplication reshaped adaptive evolution in a relict plant species, Cyclocarya paliurus
Authors: Qu Yinquan , Shang Xulan , Zeng Ziyan , Yu Yanhao , Bian Guoliang , Wang Wenling , Liu Li , Tian Li , Zhang Shengcheng , Wang Qian , Xie Dejin , Chen Xuequn , Liao Zhenyang , Wang Yibin , Qin Jian , Yang Wanxia , Sun Caowen , Fu Xiangxiang , Zhang Xingtan , Fang Shengzuo 
Published: September 2022

AbstractCyclocarya paliurus is a relict plant species that survived the last Glacial period and shows a population expansion recently. Its leaves have been traditionally used to treat obesity and diabetes with the well-known active ingredient cyclocaric acid B. Here, we present three C. paliurus genomes from two diploids with different flower morphs and one haplotype-resolved tetraploid assembly. Comparative genomic analysis revealed two rounds of recent whole-genome duplication events and identified 691 genes with dosage-effect that likely contribute to adaptive evolution through enhanced photosynthesis and increased accumulation of triterpenoids. Re-sequencing analysis of 45 accessions uncovered two bottlenecks, consistent with the known events of environmental changes, and many selectively swept genes involved in critical biological functions, including plant defense and secondary metabolism biosynthesis. We also proposed the biosynthesis pathway of cyclocaric acid B based on multi-omics data and identified key genes, in particular gibberellin related genes, associated with heterodichogamy in the species. Our research sheds light on evolutionary history and provides genomics resources to study the medicinal herb.
Production and secretion of recombinant proteins using the endotoxin-free, Gram-negative bacterium Sphingobium japonicum
Authors: Shahar Ehud , Emquies Ken , Pitcovski Jacob , Bloch Itai , Eliahu Dalia , Adiva Ran Ben , Yadid Itamar 
Published: September 2022

AbstractGram-negative bacteria are common and efficient protein expression systems, yet their outer membrane endotoxins can elicit undesirable toxic effects, limiting their applicability for parenteral therapeutic applications, e.g., production of vaccine components. In the bacterial genus Sphingomonas from the Alphaproteobacteria class, lipopolysaccharide (LPS) endotoxins are replaced with non-toxic glycosphingolipids (GSL), rendering it an attractive alternative for therapeutic protein production. To explore the use of Sphingomonas as a safe expression system for production of proteins for therapeutic applications, in this study, Sphingobium japonicum (SJ) injected live into embryonated hen eggs proved safe and nontoxic. Multimeric viral polypeptides derived from Newcastle disease virus (NDV) designed for expression in SJ, yielded soluble proteins which were specifically recognized by antibodies raised against the whole virus. In addition, native signal peptides (SP) motifs identified using whole-genome computerized analysis and coupled to secreted proteins in SJ induced secretion of αAmy and mCherry gene products. Relative to the same genes expressed without an SP, SP 104 increased secretion of αAmy (3.7-fold) and mCherry (16.3-fold) proteins and yielded accumulation of up to 80µg/L of the later in the culture medium. Taken together, the presented findings demonstrate the potential of this unique LPS-free Gram-negative bacterial family to serve as an important tool for protein expression for both research and biotechnological purposes, including for the development of novel vaccines.ImportanceThe Gram-negative, LPS-free Sphingomonas genus can serve as an effective and safe platform for therapeutic protein expression and secretion and bears potential as a live bacteria delivery system for protein vaccines.
Systematic Epigenome Editing Captures the Context-dependent Instructive Function of Chromatin Modifications
Authors: Policarpi Cristina , Munafò Marzia , Tsagkris Stylianos , Carlini Valentina , Hackett Jamie A. 
Published: September 2022

ABSTRACTChromatin modifications are linked with regulating patterns of gene expression, but their causal role and context-dependent impact on transcription remains unresolved. Here, we develop a modular epigenome editing platform that programmes nine key chromatin modifications – or combinations thereof – to precise loci in living cells. We couple this with single-cell readouts to systematically quantitate the magnitude and heterogeneity of transcriptional responses elicited by each specific chromatin modification. Amongst these, we show installing H3K4me3 at promoters causally instructs transcription activation by hierarchically remodeling the chromatin landscape. We further dissect how DNA sequence motifs influence the transcriptional impact of chromatin marks, identifying switch-like and attenuative effects within distinct cis contexts. Finally, we examine the interplay of combinatorial modifications, revealing co-targeted H3K27me3 and H2AK119ub maximise silencing penetrance across single-cells. Our precision perturbation strategy unveils the causal principles of how chromatin modification(s) influence transcription, and dissects how quantitative responses are calibrated by contextual interactions.