bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies
Authors: Yan Xin , Chen Deyun , Wang Yao , Guo Yelei , Tong Chuan , Wei Jianshu , Zhang Yajing , Wu Zhiqiang , Han Weidong 
Published: April 2022

AbstractDespite the remarkable success of chimeric antigen receptor (CAR) T-cell therapy for treating hematologic malignancies, resistance and recurrence still occur, while the markers or mechanisms underlying this resistance remain poorly understood. Here, via an unbiased genome-wide CRISPR/Cas9 screening, we identified loss of NOXA, a B-cell lymphoma 2 (BCL2) family protein in B-cell malignancies, as a pivotal regulator of resistance to CAR T-cell therapy by impairing apoptosis of tumor cells both in vitro and in vivo. Notably, low NOXA expression in tumor samples was correlated with worse survival in a tandem CD19/20 CAR T clinical trial in relapsed/refractory B-cell lymphoma. In contrast, pharmacological augmentation of NOXA expression by histone deacetylase (HDAC) inhibitors dramatically sensitized cancer cells to CAR T cell-mediated clearance in vitro and in vivo. Our work revealed the essentiality of NOXA in resistance to CAR T-cell therapy and suggested NOXA as a predictive marker for response and survival in patients receiving CAR T-cell transfusions. Pharmacological targeting of NOXA might provide an innovative therapeutic strategy to enhance CAR T-cell therapy.
Targeted protein degradation: mechanisms, strategies and application
Authors: Zhao Lin , Zhao Jia , Zhong Kunhong , Tong Aiping , Jia Da 
Published: April 2022

AbstractTraditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.
sTREM2 mediates the associations of minimal depressive symptoms with amyloid pathology in prodromal Alzheimer’s disease: The CABLE study
Authors: Wang Zhi-Bo , Sun Yan , Ma Ya-Hui , Fu Yan , Hu Hao , Xu Wei , Wang Zuo-Teng , Ma Ling-Zhi , Tan Lan , Yu Jin-Tai 
Published: April 2022

AbstractThe effects of microglial activation on the associations between depression and Alzheimer’s disease (AD) are still unclear. TREM2 gene plays a pivotal role in microglial activation, has been identified as a risk factor for AD. In this work, we aimed to assess the interrelationships of soluble TREM2 (sTREM2) level in cerebrospinal fluid (CSF), minimal depressive symptoms (MDSs), and CSF amyloid markers. The linear regression analyses were conducted on 796 cognitively unimpaired participants from the CABLE (Chinese Alzheimer’s Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were used to test the mediation effects. In addition, similar statistical analyses were performed in subgroups stratified by sex, age, and APOE ε4 carrier status. In total subjects, MDSs were associated with lower CSF sTREM2 levels (p < 0.0001), lower CSF amyloid markers (p < 0.0001), and poorer cognitive performance (MMSE, p = 0.0014). The influence of MDSs on CSF amyloid markers was partially mediated by CSF sTREM2 (proportion from 2.91 to 32.58%, p < 0.0001). And we found that the sTREM2-amyloid pathway partially mediated the effects of MDSs on cognition. Of note, exploratory subgroup analyses showed that the above influences of CSF sTREM2 were pronounced in the APOE ε4 (−) group. These results suggest that early depression is associated with amyloid pathology, which might be partly mediated by microglial activation, especially in the absence of APOE ε4.
GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt
Authors: He Yu , Pei Yufeng , Liu Kai , Liu Lin , Tian Yue , Li Hongyi , Cong Min , Liu Tianhui , Ma Hong , You Hong , Jia Jidong , Zhang Dong , Wang Ping 
Published: April 2022

AbstractHepatic stem/progenitor cells are the major cell compartment for tissue repair when hepatocyte proliferation is compromised in chronic liver diseases, but the expansion of these cells increases the risk of carcinogenesis. Therefore, it is essential to explore the pathways restricting their expansion and abnormal transformation. The ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL) showed the most highly increased expression in hepatic progenitor cells treated with transforming growth factor (TGF)-β1. If overexpressed by hepatic progenitor cells, GITRL stimulated cell proliferation by activating the epithelial–mesenchymal transition pathway and enhancing ERK1/2 and Akt phosphorylation via GITRL binding to ANXA2. However, GITR, the specific GITRL receptor, suppressed the epithelial–mesenchymal transition pathway of GITRL-expressing cells and decreased their growth by dissociating ANXA2 from GITRL and reducing downstream ERK1/2 and Akt phosphorylation. This study identifies GITR/GITRL reverse signalling as a cross-interaction pathway between immune cells and hepatic stem/progenitor cells that restricts the expansion of hepatic stem/progenitor cells and reduces the possibility of carcinogenesis.
Endogenous ROS production in early differentiation state suppresses endoderm differentiation via transient FOXC1 expression
Authors: Oka Sugako , Tsuzuki Teruhisa , Hidaka Masumi , Ohno Mizuki , Nakatsu Yoshimichi , Sekiguchi Mutsuo 
Published: April 2022

AbstractOxidative stress plays a pivotal role in the differentiation and proliferation of cells and programmed cell death. However, studies on the role of oxidative stress in differentiation have mainly employed the detection of reactive oxygen species (ROS) during differentiation or generated by ROS inducers. Therefore, it is difficult to clarify the significance of endogenous ROS production in the differentiation of human cells. We developed a system to control the intracellular level of ROS in the initial stage of differentiation in human iPS cells. By introducing a specific substitution (I69E) into the SDHC protein, a component of the mitochondrial respiratory chain complex, the endogenous ROS level increased. This caused impaired endoderm differentiation of iPS cells, and this impairment was reversed by overproduction of mitochondrial-targeted catalase, an anti-oxidant enzyme. Expression of tumor-related FOXC1 transcription factor increased transiently as early as 4 h after ROS-overproduction in the initial stage of differentiation. Knockdown of FOXC1 markedly improved impaired endoderm differentiation, suggesting that endogenous ROS production in the early differentiation state suppresses endoderm differentiation via transient FOXC1 expression.
Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function
Authors: Hinden Liad , Ahmad Majdoleen , Hamad Sharleen , Nemirovski Alina , Szanda Gergő , Glasmacher Sandra , Kogot-Levin Aviram , Abramovitch Rinat , Thorens Bernard , Gertsch Jürg , Leibowitz Gil , Tam Joseph 
Published: April 2022

AbstractActivation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.
Light-driven transition-metal-free direct decarbonylation of unstrained diaryl ketones via a dual C–C bond cleavage
Authors: Cao Dawei , Ataya Mohamad , Chen Zhangpei , Zeng Huiying , Peng Yong , Khaliullin Rustam Z. , Li Chao-Jun 
Published: April 2022

AbstractThe cleavage and formation of carbon−carbon bonds have emerged as powerful tools for structural modifications in organic synthesis. Although transition−metal−catalyzed decarbonylation of unstrained diaryl ketones provides a viable protocol to construct biaryl structures, the use of expensive catalyst and high temperature (>140 oC) have greatly limited their universal applicability. Moreover, the direct activation of two inert C − C bonds in diaryl ketones without the assistance of metal catalyst has been a great challenge due to the inherent stability of C − C bonds (nonpolar, thermo-dynamically stable, and kinetically inert). Here we report an efficient light-driven transition-metal-free strategy for decarbonylation of unstrained diaryl ketones to construct biaryl compounds through dual inert C − C bonds cleavage. This reaction featured mild reaction conditions, easy-to-handle reactants and reagents, and excellent functional groups tolerance. The mechanistic investigation and DFT calculation suggest that this strategy proceeds through the formation of dioxy radical intermediate via a single-electron-transfer (SET) process between photo-excited diaryl ketone and DBU mediated by DMSO, followed by removal of CO2 to construct biaryl compounds.
Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
Authors: Han Jian , An Omer , Ren Xi , Song Yangyang , Tang Sze Jing , Shen Haoqing , Ke Xinyu , Ng Vanessa Hui En , Tay Daryl Jin Tai , Tan Hui Qing , Kappei Dennis , Yang Henry , Chen Leilei 
Published: April 2022

AbstractThe dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development.
Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing
Authors: Frey Nina , Tortola Luigi , Egli David , Janjuha Sharan , Rothgangl Tanja , Marquart Kim Fabiano , Ampenberger Franziska , Kopf Manfred , Schwank Gerald 
Published: April 2022

AbstractPancreatic ductal adenocarcinoma (PDA) is an inherently immune cell deprived tumor, characterized by desmoplastic stroma and suppressive immune cells. Here we systematically dissect PDA intrinsic mechanisms of immune evasion by in vitro and in vivo CRISPR screening, and identify Vps4b and Rnf31 as essential factors required for escaping CD8+ T cell killing. For Vps4b we find that inactivation impairs autophagy, resulting in increased accumulation of CD8+ T cell-derived granzyme B and subsequent tumor cell lysis. For Rnf31 we demonstrate that it protects tumor cells from TNF-mediated caspase 8 cleavage and subsequent apoptosis induction, a mechanism that is conserved in human PDA organoids. Orthotopic transplantation of Vps4b- or Rnf31 deficient pancreatic tumors into immune competent mice, moreover, reveals increased CD8+ T cell infiltration and effector function, and markedly reduced tumor growth. Our work uncovers vulnerabilities in PDA that might be exploited to render these tumors more susceptible to the immune system.
Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells
Authors: Franchina Davide G. , Kurniawan Henry , Grusdat Melanie , Binsfeld Carole , Guerra Luana , Bonetti Lynn , Soriano-Baguet Leticia , Ewen Anouk , Kobayashi Takumi , Farinelle Sophie , Minafra Anna Rita , Vandamme Niels , Carpentier Anaïs , Borgmann Felix K. , Jäger Christian , Chen Ying , Kleinewietfeld Markus , Vasiliou Vasilis , Mittelbronn Michel , Hiller Karsten , Lang Philipp A. , Brenner Dirk 
Published: April 2022

AbstractThe metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically,Gclcablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore,Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally,Gclcdeficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest thatGclcis required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.
Radiationless mechanism of UV deactivation by cuticle phenolics in plants
Authors: González Moreno Ana , de Cózar Abel , Prieto Pilar , Domínguez Eva , Heredia Antonio 
Published: April 2022

AbstractHydroxycinnamic acids present in plant cuticles, the interphase and the main protective barrier between the plant and the environment, exhibit singular photochemical properties that could allow them to act as a UV shield. Here, we employ transient absorption spectroscopy on isolated cuticles and leaf epidermises to study in situ the photodynamics of these molecules in the excited state. Based on quantum chemical calculations on p-coumaric acid, the main phenolic acid present in the cuticle, we propose a model in which cuticle phenolics display a photoprotective mechanism based in an ultrafast and non-radiative excited state deactivation combined with fluorescence emission. As such, the cuticle can be regarded as the first and foremost protective barrier against UV radiation. This photostable and photodynamic mechanism seems to be universal in land plants giving a special role and function to the presence of different aromatic domains in plant cuticles and epidermises.
Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age
Authors: Mills William A. , Woo AnnaLin M. , Jiang Shan , Martin Joelle , Surendran Dayana , Bergstresser Matthew , Kimbrough Ian F. , Eyo Ukpong B. , Sofroniew Michael V. , Sontheimer Harald 
Published: April 2022

AbstractAstrocytes extend endfeet that enwrap the vasculature, and disruptions to this association which may occur in disease coincide with breaches in blood-brain barrier (BBB) integrity. Here we investigate if focal ablation of astrocytes is sufficient to disrupt the BBB in mice. Targeted two-photon chemical apoptotic ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. In young animals, replacement processes occur in advance of endfoot retraction, but this is delayed in aged animals. Stimulation of replacement astrocytes results in constriction of pre-capillary arterioles, suggesting that replacement astrocytes are functional. Pharmacological inhibition of pSTAT3, as well as astrocyte specific deletion of pSTAT3, reduces astrocyte replacement post-ablation, without perturbations to BBB integrity. Similar endfoot replacement occurs following astrocyte cell death due to reperfusion in a stroke model. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells.
Ensemble of nucleic acid absolute quantitation modules for copy number variation detection and RNA profiling
Authors: Wu Lucia Ruojia , Dai Peng , Wang Michael Xiangjiang , Chen Sherry Xi , Cohen Evan N. , Jayachandran Gitanjali , Zhang Jinny Xuemeng , Serrano Angela V. , Xie Nina Guanyi , Ueno Naoto T. , Reuben James M. , Barcenas Carlos H. , Zhang David Yu 
Published: April 2022

AbstractCurrent gold standard for absolute quantitation of a specific DNA sequence is droplet digital PCR (ddPCR), which has been applied to copy number variation (CNV) detection. However, the number of quantitation modules in ddPCR is limited by fluorescence channels, which thus limits the CNV sensitivity due to sampling error following Poisson distribution. Here we develop a PCR-based molecular barcoding NGS approach, quantitative amplicon sequencing (QASeq), for accurate absolute quantitation scalable to over 200 quantitation modules. By attaching barcodes to individual target molecules with high efficiency, 2-plex QASeq exhibits higher and more consistent conversion yield than ddPCR in absolute molecule count quantitation. Multiplexed QASeq improves CNV sensitivity allowing confident distinguishment of 2.05 ploidy from normal 2.00 ploidy. We apply multiplexed QASeq to serial longitudinal plasma cfDNA samples from patients with metastaticERBB2+ (HER2+ ) breast cancer seeking association with tumor progression. We further show an RNA QASeq panel for targeted expression profiling.
Synthesis of ternary copper antimony sulfide via solventless thermolysis or aerosol assisted chemical vapour deposition using metal dithiocarbamates
Authors: Makin Fadiyah , Alam Firoz , Buckingham Mark A. , Lewis David J. 
Published: April 2022

AbstractCopper antimony sulfide (Cu-Sb-S) has recently been proposed as an attractive alternative photovoltaic material due to the earth-abundant and non-toxic nature of the elements, high absorption coefficients and band gaps commensurate with efficient harvesting of solar photonic flux across multiple phases of Cu-Sb-S. These materials are therefore highly desirable and sustainable and scalable deposition techniques to produce them are of interest. In this paper, we demonstrate two facile, low-temperature and inexpensive techniques (solventless thermolysis and aerosol-assisted chemical vapor deposition (AACVD)) for the preparation of binary digenite (Cu1.8S), chalcocite (Cu2S) and stibnite (Sb2S3) and several phases of ternary copper-antimony-sulfide (Cu2xSb2(1−x)Sy, where 0 ≤ x ≤ 1). It was found that by utilising these different techniques and varying the ratio of Cu:Sb, pure phases of ternary chalcostibite (CuSbS2), fematinite (Cu3SbS4) and tetrahedrite (Cu12Sb4S13) can be achieved. Two single-source precursors were investigated for this purpose, namely the diethyldithiocarbamate (DTC) complexes of copper and antimony Cu(DTC)2and Sb(DTC)3. These were decomposed both individually (to produce binary materials) and combined (to produce ternary materials) at different ratios. From the solventless thermolysis and AACVD methods, either particulate or thin film material was formed, respectively. These materials were then characterised by powder XRD, SEM, EDX and Raman spectroscopies to determine the crystalline phase, material morphology and uniformity of elemental composition. This analysis demonstrated that as the Cu-content increases, the phase of the ternary material changes from chalcostibite (CuSbS2) and fematinite (Cu3SbS4) at a low Cu:Sb ratio to tetrahedrite (Cu12Sb4S13) at a high Cu:Sb ratio.
DNA methylation in peripheral tissues and left-handedness
Authors: Odintsova Veronika V. , Suderman Matthew , Hagenbeek Fiona A. , Caramaschi Doretta , Hottenga Jouke-Jan , Pool René ,   BIOS Consortium,   Management Team, Heijmans Bastiaan T. , ’t Hoen Peter A. C. , van Meurs Joyce , Isaacs Aaron , Jansen Rick , Franke Lude ,   Cohort collection, Boomsma Dorret I. , Pool René , van Dongen Jenny , Hottenga Jouke J. , van Greevenbroek Marleen M. J. , Stehouwer Coen D. A. , van der Kallen Carla J. H. , Schalkwijk Casper G. , Wijmenga Cisca , Franke Lude , Zhernakova Sasha , Tigchelaar Ettje F. , Slagboom P. Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H. , Van den Berg Leonard H. , van Duijn Cornelia M. , Hofman Bert A. , Isaacs Aaron , Uitterlinden André G. ,   Data Generation, van Meurs Joyce , Jhamai P. Mila , Verbiest Michael , Suchiman H. Eka D. , Verkerk Marijn , van der Breggen Ruud , van Rooij Jeroen , Lakenberg Nico ,   Data management and computational infrastructure, Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , Zhernakova Dasha V. , Jansen Rick , ’t Hof Peter van , Deelen Patrick , Nooren Irene , ’t Hoen Peter A. C. , Heijmans Bastiaan T. , Moed Matthijs ,   Data Analysis Group, Franke Lude , Vermaat Martijn , Zhernakova Dasha V. , Luijk René , Bonder Marc Jan , van Iterson Maarten , Deelen Patrick , van Dijk Freerk , van Galen Michiel , Arindrarto Wibowo , Kielbasa Szymon M. , Swertz Morris A. , van Zwet Erik. W. , Jansen Rick , ’t Hoen Peter-Bram , Heijmans Bastiaan T. , Dolan Conor V. , Ligthart Lannie , van Beijsterveldt Catharina E. M. , Willemsen Gonneke , de Geus Eco J. C. , Beck Jeffrey J. , Ehli Erik A. , Cuellar-Partida Gabriel , Evans David M. , Medland Sarah E. , Relton Caroline L. , Boomsma Dorret I. , van Dongen Jenny 
Published: April 2022

AbstractHandedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355–0.578]), but inconsistent across tissues (correlation range [− 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.