bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells
Authors: Aguilar Carmen , Costa Susana , Maudet Claire , Vivek-Ananth R. P. , Zaldívar-López Sara , Garrido Juan J. , Samal Areejit , Mano Miguel , Eulalio Ana 
Published: June 2021

AbstractCells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected withSalmonellaTyphimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such asShigella flexneriorListeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome ofSalmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promoteSalmonellareplication within infected cells and prime bystander cells for more efficient infection.
RNA structure probing reveals the structural basis of Dicer binding and cleavage
Authors: Luo Qing-Jun , Zhang Jinsong , Li Pan , Wang Qing , Zhang Yue , Roy-Chaudhuri Biswajoy , Xu Jianpeng , Kay Mark A. , Zhang Qiangfeng Cliff 
Published: June 2021

AbstractIt is known that an RNA’s structure determines its biological function, yet current RNA structure probing methods only capture partial structure information. The ability to measure intact (i.e., full length) RNA structures will facilitate investigations of the functions and regulation mechanisms of small RNAs and identify short fragments of functional sites. Here, we present icSHAPE-MaP, an approach combining in vivo selective 2′-hydroxyl acylation and mutational profiling to probe intact RNA structures. We further showcase the RNA structural landscape of substrates bound by human Dicer based on the combination of RNA immunoprecipitation pull-down and icSHAPE-MaP small RNA structural profiling. We discover distinct structural categories of Dicer substrates in correlation to both their binding affinity and cleavage efficiency. And by tertiary structural modeling constrained by icSHAPE-MaP RNA structural data, we find the spatial distance measuring as an influential parameter for Dicer cleavage-site selection.
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2
Authors: Pack Lindsey R. , Daigh Leighton H. , Chung Mingyu , Meyer Tobias 
Published: June 2021

AbstractSince their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors—palbociclib, ribociclib, or abemaciclib—immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.
Pathogen effector recognition-dependent association of NRG1 with EDS1 and SAG101 in TNL receptor immunity
Authors: Sun Xinhua , Lapin Dmitry , Feehan Joanna M. , Stolze Sara C. , Kramer Katharina , Dongus Joram A. , Rzemieniewski Jakub , Blanvillain-Baufumé Servane , Harzen Anne , Bautor Jaqueline , Derbyshire Paul , Menke Frank L. H. , Finkemeier Iris , Nakagami Hirofumi , Jones Jonathan D. G. , Parker Jane E. 
Published: June 2021

AbstractPlants utilise intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors to detect pathogen effectors and activate local and systemic defence. NRG1 and ADR1 “helper” NLRs (RNLs) cooperate with enhanced disease susceptibility 1 (EDS1), senescence-associated gene 101 (SAG101) and phytoalexin-deficient 4 (PAD4) lipase-like proteins to mediate signalling from TIR domain NLR receptors (TNLs). The mechanism of RNL/EDS1 family protein cooperation is not understood. Here, we present genetic and molecular evidence for exclusive EDS1/SAG101/NRG1 and EDS1/PAD4/ADR1 co-functions in TNL immunity. Using immunoprecipitation and mass spectrometry, we show effector recognition-dependent interaction of NRG1 with EDS1 and SAG101, but not PAD4. An EDS1-SAG101 complex interacts with NRG1, and EDS1-PAD4 with ADR1, in an immune-activated state. NRG1 requires an intact nucleotide-binding P-loop motif, and EDS1 a functional EP domain and its partner SAG101, for induced association and immunity. Thus, two distinct modules (NRG1/EDS1/SAG101 and ADR1/EDS1/PAD4) mediate TNL receptor defence signalling.
A multicentre validation study of the diagnostic value of plasma neurofilament light
Authors: Ashton Nicholas J. , Janelidze Shorena , Al Khleifat Ahmad , Leuzy Antoine , van der Ende Emma L. , Karikari Thomas K. , Benedet Andrea L. , Pascoal Tharick A. , Lleó Alberto , Parnetti Lucilla , Galimberti Daniela , Bonanni Laura , Pilotto Andrea , Padovani Alessandro , Lycke Jan , Novakova Lenka , Axelsson Markus , Velayudhan Latha , Rabinovici Gil D. , Miller Bruce , Pariante Carmine , Nikkheslat Naghmeh , Resnick Susan M. , Thambisetty Madhav , Schöll Michael , Fernández-Eulate Gorka , Gil-Bea Francisco J. , López de Munain Adolfo , Al-Chalabi Ammar , Rosa-Neto Pedro , Strydom Andre , Svenningsson Per , Stomrud Erik , Santillo Alexander , Aarsland Dag , van Swieten John C. , Palmqvist Sebastian , Zetterberg Henrik , Blennow Kaj , Hye Abdul , Hansson Oskar 
Published: June 2021

AbstractIncreased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
Sam68 promotes hepatic gluconeogenesis via CRTC2
Authors: Qiao Aijun , Zhou Junlan , Xu Shiyue , Ma Wenxia , Boriboun Chan , Kim Teayoun , Yan Baolong , Deng Jianxin , Yang Liu , Zhang Eric , Song Yuhua , Ma Yongchao C. , Richard Stephane , Zhang Chunxiang , Qiu Hongyu , Habegger Kirk M. , Zhang Jianyi , Qin Gangjian 
Published: June 2021

AbstractHepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.
The influence of decision-making in tree ring-based climate reconstructions
Authors: Büntgen Ulf , Allen Kathy , Anchukaitis Kevin J. , Arseneault Dominique , Boucher Étienne , Bräuning Achim , Chatterjee Snigdhansu , Cherubini Paolo , Churakova Olga V. , Corona Christophe , Gennaretti Fabio , Grießinger Jussi , Guillet Sebastian , Guiot Joel , Gunnarson Björn , Helama Samuli , Hochreuther Philipp , Hughes Malcolm K. , Huybers Peter , Kirdyanov Alexander V. , Krusic Paul J. , Ludescher Josef , Meier Wolfgang J.-H. , Myglan Vladimir S. , Nicolussi Kurt , Oppenheimer Clive , Reinig Frederick , Salzer Matthew W. , Seftigen Kristina , Stine Alexander R. , Stoffel Markus , St. George Scott , Tejedor Ernesto , Trevino Aleyda , Trouet Valerie , Wang Jianglin , Wilson Rob , Yang Bao , Xu Guobao , Esper Jan 
Published: June 2021

AbstractTree-ring chronologies underpin the majority of annually-resolved reconstructions of Common Era climate. However, they are derived using different datasets and techniques, the ramifications of which have hitherto been little explored. Here, we report the results of a double-blind experiment that yielded 15 Northern Hemisphere summer temperature reconstructions from a common network of regional tree-ring width datasets. Taken together as an ensemble, the Common Era reconstruction mean correlates with instrumental temperatures from 1794–2016 CE at 0.79 (p < 0.001), reveals summer cooling in the years following large volcanic eruptions, and exhibits strong warming since the 1980s. Differing in their mean, variance, amplitude, sensitivity, and persistence, the ensemble members demonstrate the influence of subjectivity in the reconstruction process. We therefore recommend the routine use of ensemble reconstruction approaches to provide a more consensual picture of past climate variability.
High throughput screening identifies SOX2 as a super pioneer factor that inhibits DNA methylation maintenance at its binding sites
Authors: Vanzan Ludovica , Soldati Hadrien , Ythier Victor , Anand Santosh , Braun Simon M. G. , Francis Nicole , Murr Rabih 
Published: June 2021

AbstractBinding of mammalian transcription factors (TFs) to regulatory regions is hindered by chromatin compaction and DNA methylation of their binding sites. Nevertheless, pioneer transcription factors (PFs), a distinct class of TFs, have the ability to access nucleosomal DNA, leading to nucleosome remodelling and enhanced chromatin accessibility. Whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Using a highly parallelized approach to investigate PF ability to bind methylated DNA and induce DNA demethylation, we show that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs displaying pioneering activity; while some PFs do not affect the methylation status of their binding sites, we identified PFs that can protect DNA from methylation and others that can induce DNA demethylation at methylated binding sites. We call the latter super pioneer transcription factors (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Finally, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation, an activity enhanced by the co-binding of OCT4. This finding suggests that SPFs could interfere with epigenetic memory during DNA replication.
A histone H3K4me1-specific binding protein is required for siRNA accumulation and DNA methylation at a subset of loci targeted by RNA-directed DNA methylation
Authors: Niu Qingfeng , Song Zhe , Tang Kai , Chen Lixian , Wang Lisi , Ban Ting , Guo Zhongxin , Kim Chanhong , Zhang Heng , Duan Cheng-Guo , Zhang Huiming , Zhu Jian-Kang , Du Jiamu , Lang Zhaobo 
Published: June 2021

AbstractIn plants, RNA-directed DNA methylation (RdDM) is a well-known de novo DNA methylation pathway that involves two plant-specific RNA polymerases, Pol IV and Pol V. In this study, we discovered and characterized an RdDM factor, RDM15. Through DNA methylome and genome-wide siRNA analyses, we show that RDM15 is required for RdDM-dependent DNA methylation and siRNA accumulation at a subset of RdDM target loci. We show that RDM15 contributes to Pol V-dependent downstream siRNA accumulation and interacts with NRPE3B, a subunit specific to Pol V. We also show that the C-terminal tudor domain of RDM15 specifically recognizes the histone 3 lysine 4 monomethylation (H3K4me1) mark. Structure analysis of RDM15 in complex with the H3K4me1 peptide showed that the RDM15 tudor domain specifically recognizes the monomethyllysine through an aromatic cage and a specific hydrogen bonding network; this chemical feature-based recognition mechanism differs from all previously reported monomethyllysine recognition mechanisms. RDM15 and H3K4me1 have similar genome-wide distribution patterns at RDM15-dependent RdDM target loci, establishing a link between H3K4me1 and RDM15-mediated RdDM in vivo. In summary, we have identified and characterized a histone H3K4me1-specific binding protein as an RdDM component, and structural analysis of RDM15 revealed a chemical feature-based lower methyllysine recognition mechanism.
Manifestations of metastable criticality in the long-range structure of model water glasses
Authors: Gartner Thomas E. , Torquato Salvatore , Car Roberto , Debenedetti Pablo G. 
Published: June 2021

AbstractMuch attention has been devoted to water’s metastable phase behavior, including polyamorphism (multiple amorphous solid phases), and the hypothesized liquid-liquid transition and associated critical point. However, the possible relationship between these phenomena remains incompletely understood. Using molecular dynamics simulations of the realistic TIP4P/2005 model, we found a striking signature of the liquid-liquid critical point in the structure of water glasses, manifested as a pronounced increase in long-range density fluctuations at pressures proximate to the critical pressure. By contrast, these signatures were absent in glasses of two model systems that lack a critical point. We also characterized the departure from equilibrium upon vitrification via the non-equilibrium index; water-like systems exhibited a strong pressure dependence in this metric, whereas simple liquids did not. These results reflect a surprising relationship between the metastable equilibrium phenomenon of liquid-liquid criticality and the non-equilibrium structure of glassy water, with implications for our understanding of water phase behavior and glass physics. Our calculations suggest a possible experimental route to probing the existence of the liquid-liquid transition in water and other fluids.
Synthetic extracellular matrices with tailored adhesiveness and degradability support lumen formation during angiogenic sprouting
Authors: Liu Jifeng , Long Hongyan , Zeuschner Dagmar , Räder Andreas F. B. , Polacheck William J. , Kessler Horst , Sorokin Lydia , Trappmann Britta 
Published: June 2021

AbstractA major deficit in tissue engineering strategies is the lack of materials that promote angiogenesis, wherein endothelial cells from the host vasculature invade the implanted matrix to form new blood vessels. To determine the material properties that regulate angiogenesis, we have developed a microfluidic in vitro model in which chemokine-guided endothelial cell sprouting into a tunable hydrogel is followed by the formation of perfusable lumens. We show that long, perfusable tubes only develop if hydrogel adhesiveness and degradability are fine-tuned to support the initial collective invasion of endothelial cells and, at the same time, allow for matrix remodeling to permit the opening of lumens. These studies provide a better understanding of how cell-matrix interactions regulate angiogenesis and, therefore, constitute an important step towards optimal design criteria for tissue-engineered materials that require vascularization.
The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating myosin II
Authors: Nakatani Takeshi , Tsujimoto Kohei , Park JeongHoon , Jo Tatsunori , Kimura Tetsuya , Hayama Yoshitomo , Konaka Hachiro , Morita Takayoshi , Kato Yasuhiro , Nishide Masayuki , Koyama Shyohei , Nada Shigeyuki , Okada Masato , Takamatsu Hyota , Kumanogoh Atsushi 
Published: June 2021

AbstractLysosomes are involved in nutrient sensing via the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is tethered to lysosomes by the Ragulator complex, a heteropentamer in which Lamtor1 wraps around Lamtor2–5. Although the Ragulator complex is required for cell migration, the mechanisms by which it participates in cell motility remain unknown. Here, we show that lysosomes move to the uropod in motile cells, providing the platform where Lamtor1 interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and MYPT1, a subunit of myosin light chain phosphatase (MLCP), thereby increasing myosin II–mediated actomyosin contraction. Additionally, formation of the complete Ragulator complex is required for leukocyte migration and pathophysiological immune responses. Together, our findings demonstrate that the lysosomal Ragulator complex plays an essential role in leukocyte migration by activating myosin II through interacting with MPRIP.
A deep learning approach to identify gene targets of a therapeutic for human splicing disorders
Authors: Gao Dadi , Morini Elisabetta , Salani Monica , Krauson Aram J. , Chekuri Anil , Sharma Neeraj , Ragavendran Ashok , Erdin Serkan , Logan Emily M. , Li Wencheng , Dakka Amal , Narasimhan Jana , Zhao Xin , Naryshkin Nikolai , Trotta Christopher R. , Effenberger Kerstin A. , Woll Matthew G. , Gabbeta Vijayalakshmi , Karp Gary , Yu Yong , Johnson Graham , Paquette William D. , Cutting Garry R. , Talkowski Michael E. , Slaugenhaupt Susan A. 
Published: June 2021

AbstractPre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.
Quantitative single-cell proteomics as a tool to characterize cellular hierarchies
Authors: Schoof Erwin M. , Furtwängler Benjamin , Üresin Nil , Rapin Nicolas , Savickas Simonas , Gentil Coline , Lechman Eric , Keller Ulrich auf dem , Dick John E. , Porse Bo T. 
Published: June 2021

AbstractLarge-scale single-cell analyses are of fundamental importance in order to capture biological heterogeneity within complex cell systems, but have largely been limited to RNA-based technologies. Here we present a comprehensive benchmarked experimental and computational workflow, which establishes global single-cell mass spectrometry-based proteomics as a tool for large-scale single-cell analyses. By exploiting a primary leukemia model system, we demonstrate both through pre-enrichment of cell populations and through a non-enriched unbiased approach that our workflow enables the exploration of cellular heterogeneity within this aberrant developmental hierarchy. Our approach is capable of consistently quantifying ~1000 proteins per cell across thousands of individual cells using limited instrument time. Furthermore, we develop a computational workflow (SCeptre) that effectively normalizes the data, integrates available FACS data and facilitates downstream analysis. The approach presented here lays a foundation for implementing global single-cell proteomics studies across the world.
Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
Authors: Babu Maria , Favretto Filippo , de Opakua Alain Ibáñez , Rankovic Marija , Becker Stefan , Zweckstetter Markus 
Published: June 2021

AbstractAmyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of theC9ORF72gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis inC9orf72-associated neurodegenerative diseases.