bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma
Authors: Garcia-Marquez Maria A. , Thelen Martin , Reinke Sarah , Keller Diandra , Wennhold Kerstin , Lehmann Jonas , Veldman Johanna , Borchmann Sven , Rosenwald Andreas , Sasse Stephanie , Diepstra Arjan , Borchmann Peter , Engert Andreas , Klapper Wolfram , von Bergwelt-Baildon Michael , Bröckelmann Paul J. , Schlößer Hans A. 
Published: September 2021

AbstractWhile classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL.
USP28 facilitates pancreatic cancer progression through activation of Wnt/β-catenin pathway via stabilising FOXM1
Authors: Chen Leifeng , Xu Zheng , Li Qing , Feng Qian , Zheng Cihua , Du Yunyan , Yuan Rongfa , Peng Xiaogang 
Published: September 2021

AbstractUbiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/β-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus β-catenin trans-activation, which in turn led to the activation of the Wnt/β-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/β-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.
Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells
Authors: Yang Wen-Bin , Wu An-Chih , Hsu Tsung-I , Liou Jing-Ping , Lo Wei-Lun , Chang Kwang-Yu , Chen Pin-Yuan , Kikkawa Ushio , Yang Shung-Tai , Kao Tzu-Jen , Chen Ruei-Ming , Chang Wen-Chang , Ko Chiung-Yuan , Chuang Jian-Ying 
Published: September 2021

AbstractDNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy.
Dynamics of TCR repertoire and T cell function in COVID-19 convalescent individuals
Authors: Luo Lingjie , Liang Wenhua , Pang Jianfeng , Xu Gang , Chen Yingying , Guo Xinrong , Wang Xin , Zhao Yi , Lai Yangdian , Liu Yang , Li Bin , Su Bing , Zhang Shuye , Baniyash Michal , Shen Lei , Chen Lei , Ling Yun , Wang Ying , Liang Qiming , Lu Hongzhou , Zhang Zheng , Wang Feng 
Published: September 2021

AbstractSARS-CoV-2 outbreak has been declared by World Health Organization as a worldwide pandemic. However, there are many unknowns about the antigen-specific T-cell-mediated immune responses to SARS-CoV-2 infection. Here, we present both single-cell TCR-seq and RNA-seq to analyze the dynamics of TCR repertoire and immune metabolic functions of blood T cells collected from recently discharged COVID-19 patients. We found that while the diversity of TCR repertoire was increased in discharged patients, it returned to basal level ~1 week after becoming virus-free. The dynamics of T cell repertoire correlated with a profound shift of gene signatures from antiviral response to metabolism adaptation. We also demonstrated that the top expanded T cell clones (~10% of total T cells) display the key anti-viral features in CD8+ T cells, confirming a critical role of antigen-specific T cells in fighting against SARS-CoV-2. Our work provides a basis for further analysis of adaptive immunity in COVID-19 patients, and also has implications in developing a T-cell-based vaccine for SARS-CoV-2.
Thiocysteine lyases as polyketide synthase domains installing hydropersulfide into natural products and a hydropersulfide methyltransferase
Authors: Meng Song , Steele Andrew D. , Yan Wei , Pan Guohui , Kalkreuter Edward , Liu Yu-Chen , Xu Zhengren , Shen Ben 
Published: September 2021

AbstractNature forms S-S bonds by oxidizing two sulfhydryl groups, and no enzyme installing an intact hydropersulfide (-SSH) group into a natural product has been identified to date. The leinamycin (LNM) family of natural products features intact S-S bonds, and previously we reported an SH domain (LnmJ-SH) within the LNM hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line as a cysteine lyase that plays a role in sulfur incorporation. Here we report the characterization of an S-adenosyl methionine (SAM)-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin (GNM) biosynthesis, discovery of hydropersulfides as the nascent products of the GNM and LNM hybrid NRPS-PKS assembly lines, and revelation of three SH domains (GnmT-SH, LnmJ-SH, and WsmR-SH) within the GNM, LNM, and weishanmycin (WSM) hybrid NRPS-PKS assembly lines as thiocysteine lyases. Based on these findings, we propose a biosynthetic model for the LNM family of natural products, featuring thiocysteine lyases as PKS domains that directly install a -SSH group into the GNM, LNM, or WSM polyketide scaffold. Genome mining reveals that SH domains are widespread in Nature, extending beyond the LNM family of natural products. The SH domains could also be leveraged as biocatalysts to install an -SSH group into other biologically relevant scaffolds.
Probabilistic tsunami forecasting for early warning
Authors: Selva J. , Lorito S. , Volpe M. , Romano F. , Tonini R. , Perfetti P. , Bernardi F. , Taroni M. , Scala A. , Babeyko A. , Løvholt F. , Gibbons S. J. , Macías J. , Castro M. J. , González-Vida J. M. , Sánchez-Linares C. , Bayraktar H. B. , Basili R. , Maesano F. E. , Tiberti M. M. , Mele F. , Piatanesi A. , Amato A. 
Published: September 2021

AbstractTsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types.
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
Authors: Ottema Sophie , Mulet-Lazaro Roger , Erpelinck-Verschueren Claudia , van Herk Stanley , Havermans Marije , Arricibita Varea Andrea , Vermeulen Michael , Beverloo H. Berna , Gröschel Stefan , Haferlach Torsten , Haferlach Claudia , J. Wouters Bas , Bindels Eric , Smeenk Leonie , Delwel Ruud 
Published: September 2021

AbstractChromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.
Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice
Authors: Hamza Bashar , Miller Alex B. , Meier Lara , Stockslager Max , Ng Sheng Rong , King Emily M. , Lin Lin , DeGouveia Kelsey L. , Mulugeta Nolawit , Calistri Nicholas L. , Strouf Haley , Bray Christina , Rodriguez Felicia , Freed-Pastor William A. , Chin Christopher R. , Jaramillo Grissel C. , Burger Megan L. , Weinberg Robert A. , Shalek Alex K. , Jacks Tyler , Manalis Scott R. 
Published: September 2021

AbstractExisting preclinical methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) en route to forming metastases have not been capable of providing a direct measure of CTC intravasation rate and subsequent half-life in the circulation. Here, we demonstrate an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood over several hours between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts. By tracking CTC transfer rates, we extrapolated half-life times in the circulation of between 40 and 260 s and intravasation rates between 60 and 107,000 CTCs/hour in mouse models of small-cell lung cancer (SCLC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). Additionally, direct transfer of only 1−2% of daily-shed CTCs using our blood-exchange technique from late-stage, SCLC-bearing mice generated macrometastases in healthy recipient mice. We envision that our technique will help further elucidate the role of CTCs and the rate-limiting steps in metastasis.
Conserved and species-specific chromatin remodeling and regulatory dynamics during mouse and chicken limb bud development
Authors: Jhanwar Shalu , Malkmus Jonas , Stolte Jens , Romashkina Olga , Zuniga Aimée , Zeller Rolf 
Published: September 2021

AbstractChromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. The analysis of mouse and chicken limb development provides important insights into the morphoregulatory mechanisms, however little is known about the regulatory differences underlying their morphological divergence. Here, we identify the underlying shared and species-specific epigenomic and genomic variations. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. In silico mapping of transcription factor binding sites and computational footprinting establishes the developmental time-restricted transcription factor-DNA interactions. Finally, the construction of target gene networks for HAND2 and GLI3 transcriptional regulators reveals both conserved and species-specific interactions. Our analysis reveals the impact of genome evolution on the regulatory interactions orchestrating vertebrate limb bud morphogenesis and provides a molecular framework for comparative Evo-Devo studies.
Supercoiling and looping promote DNA base accessibility and coordination among distant sites
Authors: Fogg Jonathan M. , Judge Allison K. , Stricker Erik , Chan Hilda L. , Zechiedrich Lynn 
Published: September 2021

AbstractDNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential processes, and how cells may use DNA loops to position nicks to facilitate repair. Furthermore, our results reveal a complex interplay between site-specific disruptions to base pairing and the 3-D conformation of DNA, which influences how genomes are stored, replicated, transcribed, repaired, and many other aspects of DNA activity.
Exceptional topological insulators
Authors: Denner M. Michael , Skurativska Anastasiia , Schindler Frank , Fischer Mark H. , Thomale Ronny , Bzdušek Tomáš , Neupert Titus 
Published: September 2021

AbstractWe introduce the exceptional topological insulator (ETI), a non-Hermitian topological state of matter that features exotic non-Hermitian surface states which can only exist within the three-dimensional topological bulk embedding. We show how this phase can evolve from a Weyl semimetal or Hermitian three-dimensional topological insulator close to criticality when quasiparticles acquire a finite lifetime. The ETI does not require any symmetry to be stabilized. It is characterized by a bulk energy point gap, and exhibits robust surface states that cover the bulk gap as a single sheet of complex eigenvalues or with a single exceptional point. The ETI can be induced universally in gapless solid-state systems, thereby setting a paradigm for non-Hermitian topological matter.
Confronting false discoveries in single-cell differential expression
Authors: Squair Jordan W. , Gautier Matthieu , Kathe Claudia , Anderson Mark A. , James Nicholas D. , Hutson Thomas H. , Hudelle Rémi , Qaiser Taha , Matson Kaya J. E. , Barraud Quentin , Levine Ariel J. , La Manno Gioele , Skinnider Michael A. , Courtine Grégoire 
Published: September 2021

AbstractDifferential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.
The identification of grain size genes by RapMap reveals directional selection during rice domestication
Authors: Zhang Juncheng , Zhang Dejian , Fan Yawei , Li Cuicui , Xu Pengkun , Li Wei , Sun Qi , Huang Xiaodong , Zhang Chunyu , Wu Linyue , Yang Huaizhou , Wang Shiyu , Su Xiaomin , Li Xingxing , Song Yingying , Wu Meng-en , Lian Xingming , Li Yibo 
Published: September 2021

AbstractCloning quantitative trait locus (QTL) is time consuming and laborious, which hinders the understanding of natural variation and genetic diversity. Here, we introduce RapMap, a method for rapid multi-QTL mapping by employing F2gradient populations (F2GPs) constructed by minor-phenotypic-difference accessions. The co-segregation standard of the single-locus genetic models ensures simultaneous integration of a three-in-one framework in RapMap i.e. detecting a real QTL, confirming its effect, and obtaining its near-isogenic line-like line (NIL-LL). We demonstrate the feasibility of RapMap by cloning eight rice grain-size genes using 15 F2GPs in three years. These genes explain a total of 75% of grain shape variation. Allele frequency analysis of these genes using a large germplasm collection reveals directional selection of the slender and long grains inindicarice domestication. In addition, major grain-size genes have been strongly selected during rice domestication. We think application of RapMap in crops will accelerate gene discovery and genomic breeding.
Self-regulated co-assembly of soft and hard nanoparticles
Authors: Cui Yan , Zhu Hongyan , Cai Jiandong , Qiu Huibin 
Published: September 2021

AbstractControlled self-assembly of colloidal particles into predetermined organization facilitates the bottom-up manufacture of artificial materials with designated hierarchies and synergistically integrated functionalities. However, it remains a major challenge to assemble individual nanoparticles with minimal building instructions in a programmable fashion due to the lack of directional interactions. Here, we develop a general paradigm for controlled co-assembly of soft block copolymer micelles and simple unvarnished hard nanoparticles through variable noncovalent interactions, including hydrogen bonding and coordination interactions. Upon association, the hairy micelle corona binds with the hard nanoparticles with a specific valence depending exactly on their relative size and feeding ratio. This permits the integration of block copolymer micelles with a diverse array of hard nanoparticles with tunable chemistry into multidimensional colloidal molecules and polymers. Secondary co-assembly of the resulting colloidal molecules further leads to the formation of more complex hierarchical colloidal superstructures. Notably, such colloidal assembly is processible on surface either through initiating the alternating co-assembly from a micelle immobilized on a substrate or directly grafting a colloidal oligomer onto the micellar anchor.
Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE
Authors: Wang Weiguang , Tsirulnikov Kirill , Zhekova Hristina R. , Kayık Gülru , Khan Hanif Muhammad , Azimov Rustam , Abuladze Natalia , Kao Liyo , Newman Debbie , Noskov Sergei Yu. , Zhou Z. Hong , Pushkin Alexander , Kurtz Ira 
Published: September 2021

AbstractSLC4 transporters play significant roles in pH regulation and cellular sodium transport. The previously solved structures of the outward facing (OF) conformation for AE1 (SLC4A1) and NBCe1 (SLC4A4) transporters revealed an identical overall fold despite their different transport modes (chloride/bicarbonate exchange versus sodium-carbonate cotransport). However, the exact mechanism determining the different transport modes in the SLC4 family remains unknown. In this work, we report the cryo-EM 3.4 Å structure of the OF conformation of NDCBE (SLC4A8), which shares transport properties with both AE1 and NBCe1 by mediating the electroneutral exchange of sodium-carbonate with chloride. This structure features a fully resolved extracellular loop 3 and well-defined densities corresponding to sodium and carbonate ions in the tentative substrate binding pocket. Further, we combine computational modeling with functional studies to unravel the molecular determinants involved in NDCBE and SLC4 transport.
In vivo structure and dynamics of the SARS-CoV-2 RNA genome
Authors: Zhang Yan , Huang Kun , Xie Dejian , Lau Jian You , Shen Wenlong , Li Ping , Wang Dong , Zou Zhong , Shi Shu , Ren Hongguang , Wang Youliang , Mao Youzhi , Jin Meilin , Kudla Grzegorz , Zhao Zhihu 
Published: September 2021

AbstractThe dynamics of SARS-CoV-2 RNA structure and their functional relevance are largely unknown. Here we develop a simplified SPLASH assay and comprehensively map the in vivo RNA-RNA interactome of SARS-CoV-2 genome across viral life cycle. We report canonical and alternative structures including 5′-UTR and 3′-UTR, frameshifting element (FSE) pseudoknot and genome cyclization in both cells and virions. We provide direct evidence of interactions between Transcription Regulating Sequences, which facilitate discontinuous transcription. In addition, we reveal alternative short and long distance arches around FSE. More importantly, we find that within virions, while SARS-CoV-2 genome RNA undergoes intensive compaction, genome domains remain stable but with strengthened demarcation of local domains and weakened global cyclization. Taken together, our analysis reveals the structural basis for the regulation of replication, discontinuous transcription and translational frameshifting, the alternative conformations and the maintenance of global genome organization during the whole life cycle of SARS-CoV-2, which we anticipate will help develop better antiviral strategies.