bluuebunny/crossref_metadata_2025_split huggingface dataset:
Moderate DNA hypomethylation suppresses intestinal tumorigenesis by promoting caspase-3 expression and apoptosis
Authors: Duan Xiaoya , Huang Yuanyong , Chen Xiaoxing , Wang Wencai , Chen Jiwei , Li Jialun , Yang Wei , Li Jiwen , Wu Qihan , Wong Jiemin 
Published: May 2021

AbstractGlobal DNA hypomethylation is a most common epigenetic alteration in human neoplasia. However, accumulative evidence shows that global DNA hypomethylation impacts tumorigenesis in a tissue-specific manner, promoting tumorigenesis in some but suppressing tumorigenesis in others including colorectal cancer. The underlying mechanisms, especially how DNA hypomethylation suppresses tumorigenesis, remain largely unknown. Here, we investigate how DNA hypomethylation affects intestinal tumorigenesis by using anUhrf1tandem tudor domain knockin mutant mouse model (Uhrf1ki/ki) that exhibits a moderate ~10% reduction of global DNA methylation. We found that both chemical-induced colorectal carcinogenesis andApcloss of heterozygosity (LOH)-induced intestinal tumorigenesis are substantially suppressed in theUhrf1mutant mice. Furthermore, unlikeDnmt1hypomorphic mice in which DNA hypomethylation suppresses the incidence of macroscopic intestinal tumors but promotes the formation of microadenoma inApcMin/+background,Uhrf1ki/ki/ApcMin/+mice have markedly reduced incidence of both microadenoma and macroadenoma. DNA hypomethylation does not appear to affectApcLOH, activation of the Wnt or Hippo pathway, or tumor cell proliferation, but acts cooperatively with activated Wnt pathway to enhance the caspase-3 gene expression, activation, and apoptosis. Furthermore, increased caspase-3 expression correlates with DNA hypomethylation within the caspase-3 enhancer regions. Taken together, we present a new mouse model for investigating the role of and the molecular mechanisms by which DNA hypomethylation suppresses intestinal tumorigenesis. Our finding that a moderate DNA hypomethylation is sufficient to suppress intestinal tumorigenesis by promoting caspase-3 expression and apoptosis sheds new light on DNA-methylation inhibitor-based colorectal cancer therapeutics.
Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition
Authors: Gao Jie , Liu Ruiqiong , Feng Dandan , Huang Wei , Huo Miaomiao , Zhang Jingyao , Leng Shuai , Yang Yang , Yang Tianshu , Yin Xin , Teng Xu , Yu Hefen , Yuan Baowen , Wang Yan 
Published: May 2021

AbstractThe biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.
E3 ligase TRIM25 ubiquitinates RIP3 to inhibit TNF induced cell necrosis
Authors: Mei Pucheng , Xie Feiyan , Pan Jiasong , Wang Sen , Gao Wenqing , Ge Rui , Gao Baocai , Gao Siqi , Chen Xiangjun , Wang Yongming , Wu Jiaxue , Ding Chen , Li Jixi 
Published: May 2021

AbstractReceptor interacting protein kinase 3 (RIP3 or RIPK3), the critical executor of cell programmed necrosis, plays essential roles in maintaining immune responses and appropriate tissue homeostasis. Although the E3 ligases CHIP and PELI1 are reported to promote RIP3 degradation, however, how post-translational modification regulates RIP3 activity and stability is poorly understood. Here, we identify the tripartite motif protein TRIM25 as a negative regulator of RIP3-dependent necrosis. TRIM25 directly interacts with RIP3 through its SPRY domain and mediates the K48-linked polyubiquitination of RIP3 on residue K501. The RING domain of TRIM25 facilitates the polyubiquitination chain on RIP3, thereby promoting proteasomal degradation of RIP3. Also, TRIM25 deficiency inhibited the ubiquitination of RIP3, thus promoting TNF-induced cell necrosis. Our current finding reveals the regulating mechanism of polyubiquitination on RIP3, which might be a potential therapeutic target for the intervention of RIP3-dependent necrosis-related diseases.
Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis
Authors: Wang Peina , Cui Yanmei , Ren Qianqian , Yan Bingqi , Zhao Yashuo , Yu Peng , Gao Guofen , Shi Honglian , Chang Shiyang , Chang Yan-Zhong 
Published: May 2021

AbstractIschaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.
Stimulation of α7-nAChRs coordinates autophagy and apoptosis signaling in experimental knee osteoarthritis
Authors: Liu Yuan , Xu Shi , Zhang Haijun , Qian Kaoliang , Huang Jiachen , Gu Xianger , Li Yan , Fan Yi , Hu Jun 
Published: May 2021

AbstractOsteoarthritis (OA) is the most common chronic joint disease in the elderly population. Growing evidence indicates that a balance between autophagy and apoptosis in chondrocytes plays a key role in OA’s cartilage degradation. Thus, drugs targeting the balance between apoptosis and autophagy are potential therapeutic approaches for OA treatment. In previous studies, we found that the activation of α7 nicotinic acetylcholine receptors (α7-nAChRs) alleviated monosodium iodoacetate (MIA)-induced joint degradation and osteoarthritis pain. To explore the potential functions of α7-nAChRs in autophagy and apoptosis signaling in knee OA, we compared the expression of α7-nAChRs in human knee articular cartilage tissues from normal humans and OA patients. We found that knee joint cartilage tissues of OA patients showed decreased α7-nAChRs and an imbalance between autophagy and apoptosis. Next, we observed that α7-nAChRs deficiency did not affect cartilage degradation in OA development but reversed the beneficial effects of nicotine on mechanical allodynia, cartilage degradation, and an MIA-induced switch from autophagy to apoptosis. Unlike in vivo studies, we found that primary chondrocytes from α7-nAChRs knockout (KO) mice showed decreased LC3 levels under normal conditions and were more sensitive toward MIA-induced apoptosis. Finally, we found that α7-nAChRs deficiency increased the phosphorylation of mTOR after MIA treatment, which can also be observed in OA patients’ tissues. Thus, our findings not only confirmed that nicotine alleviated MIA-induced pain behavior and cartilage degradation via stimulating the α7-nAChRs/mTOR signal pathway but found the potential role of α7-nAChRs in mediating the balance between apoptosis and autophagy.
Single-cell analysis reveals urothelial cell heterogeneity and regenerative cues following cyclophosphamide-induced bladder injury
Authors: Cheng Xiaomu , Lai Huadong , Luo Wenqin , Zhang Man , Miao Juju , Song Weichen , Xing Shunpeng , Wang Jia , Gao Wei-Qiang 
Published: May 2021

AbstractCyclophosphamide is a commonly used chemotherapeutic drug to treat cancer with side effects that trigger bladder injury and hemorrhagic cystitis. Although previous studies have demonstrated that certain cell subsets and communications are activated to drive the repair and regeneration of bladder, it is not well understood how distinct bladder cell subsets function synergistically in this process. Here, we used droplet-based single-cell RNA sequencing (scRNA-seq) to profile the cell types within the murine bladder mucous layer under normal and injured conditions. Our analysis showed that superficial cells are directly repaired by cycling intermediate cells. We further identified two resident mesenchymal lineages (Acta2+ myofibroblasts and Cd34+ fibroblasts). The delineation of cell-cell communications revealed that Acta2+ myofibroblasts upregulated Fgf7 expression during acute injury, which activated Fgfr signaling in progenitor cells within the basal/intermediate layers to promote urothelial cell growth and repair. Overall, our study contributes to a more comprehensive understanding of the cellular dynamics during cyclophosphamide-induced bladder injury and may help identify important niche factors contributing to the regeneration of injured bladders.
Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation
Authors: Yin Yun-Nian , Ding Rui-Qi , Ouyang Dong-Chen , Zhang Qing , Zhu Rong 
Published: May 2021

Abstractα-Tertiary amides are of great importance for medicinal chemistry. However, they are often challenging to access through conventional methods due to reactivity and chemoselectivity issues. Here, we report a single-step approach towards such amides via cobalt-catalyzed intermolecular oxidative hydroamidation of unactivated alkenes, using nitriles of either solvent- or reagent-quantities. This protocol is selective for terminal alkenes over groups that rapidly react under known carbocation amidation conditions such as tertiary alcohols, electron-rich alkenes, ketals, weak C−H bonds, and carboxylic acids. Straightforward access to a diverse array of hindered amides is demonstrated, including a rapid synthesis of an aminoadamantane-derived pharmaceutical intermediate.
Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
Authors: Youlten Scott E. , Kemp John P. , Logan John G. , Ghirardello Elena J. , Sergio Claudio M. , Dack Michael R. G. , Guilfoyle Siobhan E. , Leitch Victoria D. , Butterfield Natalie C. , Komla-Ebri Davide , Chai Ryan C. , Corr Alexander P. , Smith James T. , Mohanty Sindhu T. , Morris John A. , McDonald Michelle M. , Quinn Julian M. W. , McGlade Amelia R. , Bartonicek Nenad , Jansson Matt , Hatzikotoulas Konstantinos , Irving Melita D. , Beleza-Meireles Ana , Rivadeneira Fernando , Duncan Emma , Richards J. Brent , Adams David J. , Lelliott Christopher J. , Brink Robert , Phan Tri Giang , Eisman John A. , Evans David M. , Zeggini Eleftheria , Baldock Paul A. , Bassett J. H. Duncan , Williams Graham R. , Croucher Peter I. 
Published: May 2021

AbstractOsteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
A data-independent acquisition-based global phosphoproteomics system enables deep profiling
Authors: Kitata Reta Birhanu , Choong Wai-Kok , Tsai Chia-Feng , Lin Pei-Yi , Chen Bo-Shiun , Chang Yun-Chien , Nesvizhskii Alexey I. , Sung Ting-Yi , Chen Yu-Ju 
Published: May 2021

AbstractPhosphoproteomics can provide insights into cellular signaling dynamics. To achieve deep and robust quantitative phosphoproteomics profiling for minute amounts of sample, we here develop a global phosphoproteomics strategy based on data-independent acquisition (DIA) mass spectrometry and hybrid spectral libraries derived from data-dependent acquisition (DDA) and DIA data. Benchmarking the method using 166 synthetic phosphopeptides shows high sensitivity (<0.1 ng), accurate site localization and reproducible quantification (~5% median coefficient of variation). As a proof-of-concept, we use lung cancer cell lines and patient-derived tissue to construct a hybrid phosphoproteome spectral library covering 159,524 phosphopeptides (88,107 phosphosites). Based on this library, our single-shot streamlined DIA workflow quantifies 36,350 phosphosites (19,755 class 1) in cell line samples within two hours. Application to drug-resistant cells and patient-derived lung cancer tissues delineates site-specific phosphorylation events associated with resistance and tumor progression, showing that our workflow enables the characterization of phosphorylation signaling with deep coverage, high sensitivity and low between-run missing values.
PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions
Authors: Ercolano Giuseppe , Gomez-Cadena Alejandra , Dumauthioz Nina , Vanoni Giulia , Kreutzfeldt Mario , Wyss Tania , Michalik Liliane , Loyon Romain , Ianaro Angela , Ho Ping-Chih , Borg Christophe , Kopf Manfred , Merkler Doron , Krebs Philippe , Romero Pedro , Trabanelli Sara , Jandus Camilla 
Published: May 2021

AbstractGroup 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.
Tunneling current modulation in atomically precise graphene nanoribbon heterojunctions
Authors: Senkovskiy Boris V. , Nenashev Alexey V. , Alavi Seyed K. , Falke Yannic , Hell Martin , Bampoulis Pantelis , Rybkovskiy Dmitry V. , Usachov Dmitry Yu. , Fedorov Alexander V. , Chernov Alexander I. , Gebhard Florian , Meerholz Klaus , Hertel Dirk , Arita Masashi , Okuda Taichi , Miyamoto Koji , Shimada Kenya , Fischer Felix R. , Michely Thomas , Baranovskii Sergei D. , Lindfors Klas , Szkopek Thomas , Grüneis Alexander 
Published: May 2021

AbstractLateral heterojunctions of atomically precise graphene nanoribbons (GNRs) hold promise for applications in nanotechnology, yet their charge transport and most of the spectroscopic properties have not been investigated. Here, we synthesize a monolayer of multiple aligned heterojunctions consisting of quasi-metallic and wide-bandgap GNRs, and report characterization by scanning tunneling microscopy, angle-resolved photoemission, Raman spectroscopy, and charge transport. Comprehensive transport measurements as a function of bias and gate voltages, channel length, and temperature reveal that charge transport is dictated by tunneling through the potential barriers formed by wide-bandgap GNR segments. The current-voltage characteristics are in agreement with calculations of tunneling conductance through asymmetric barriers. We fabricate a GNR heterojunctions based sensor and demonstrate greatly improved sensitivity to adsorbates compared to graphene based sensors. This is achieved via modulation of the GNR heterojunction tunneling barriers by adsorbates.
Co-occupancy identifies transcription factor co-operation for axon growth
Authors: Venkatesh Ishwariya , Mehra Vatsal , Wang Zimei , Simpson Matthew T. , Eastwood Erik , Chakraborty Advaita , Beine Zac , Gross Derek , Cabahug Michael , Olson Greta , Blackmore Murray G. 
Published: May 2021

AbstractTranscription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.
Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling
Authors: Lee Wei Ting C. , Yin Yandong , Morten Michael J. , Tonzi Peter , Gwo Pam Pam , Odermatt Diana C. , Modesti Mauro , Cantor Sharon B. , Gari Kerstin , Huang Tony T. , Rothenberg Eli 
Published: May 2021

AbstractGuanine-rich DNA sequences occur throughout the human genome and can transiently form G-quadruplex (G4) structures that may obstruct DNA replication, leading to genomic instability. Here, we apply multi-color single-molecule localization microscopy (SMLM) coupled with robust data-mining algorithms to quantitatively visualize replication fork (RF)-coupled formation and spatial-association of endogenous G4s. Using this data, we investigate the effects of G4s on replisome dynamics and organization. We show that a small fraction of active replication forks spontaneously form G4s at newly unwound DNA immediately behind the MCM helicase and before nascent DNA synthesis. These G4s locally perturb replisome dynamics and organization by reducing DNA synthesis and limiting the binding of the single-strand DNA-binding protein RPA. We find that the resolution of RF-coupled G4s is mediated by an interplay between RPA and the FANCJ helicase. FANCJ deficiency leads to G4 accumulation, DNA damage at G4-associated replication forks, and silencing of the RPA-mediated replication stress response. Our study provides first-hand evidence of the intrinsic, RF-coupled formation of G4 structures, offering unique mechanistic insights into the interference and regulation of stable G4s at replication forks and their effect on RPA-associated fork signaling and genomic instability.
Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
Authors: Lee Eunhye , Bujalowski Paul J. , Teramoto Tadahisa , Gottipati Keerthi , Scott Seth D. , Padmanabhan Radhakrishnan , Choi Kyung H. 
Published: May 2021

AbstractFlaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5′ end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5′ guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism.
Deep generative model embedding of single-cell RNA-Seq profiles on hyperspheres and hyperbolic spaces
Authors: Ding Jiarui , Regev Aviv 
Published: May 2021

AbstractSingle-cell RNA-Seq (scRNA-seq) is invaluable for studying biological systems. Dimensionality reduction is a crucial step in interpreting the relation between cells in scRNA-seq data. However, current dimensionality reduction methods are often confounded by multiple simultaneous technical and biological variability, result in “crowding” of cells in the center of the latent space, or inadequately capture temporal relationships. Here, we introduce scPhere, a scalable deep generative model to embed cells into low-dimensional hyperspherical or hyperbolic spaces to accurately represent scRNA-seq data. ScPhere addresses multi-level, complex batch factors, facilitates the interactive visualization of large datasets, resolves cell crowding, and uncovers temporal trajectories. We demonstrate scPhere on nine large datasets in complex tissue from human patients or animal development. Our results show how scPhere facilitates the interpretation of scRNA-seq data by generating batch-invariant embeddings to map data from new individuals, identifies cell types affected by biological variables, infers cells’ spatial positions in pre-defined biological specimens, and highlights complex cellular relations.