bluuebunny/crossref_metadata_2025_split huggingface dataset:
PARP14 is a novel target in STAT6 mutant follicular lymphoma
Authors: Mentz Michael , Keay William , Strobl Carolin Dorothea , Antoniolli Martina , Adolph Louisa , Heide Michael , Lechner Axel , Haebe Sarah , Osterode Elisa , Kridel Robert , Ziegenhain Christoph , Wange Lucas Esteban , Hildebrand Johannes Adrian , Shree Tanaya , Silkenstedt Elisabeth , Staiger Annette M. , Ott German , Horn Heike , Szczepanowski Monika , Richter Julia , Levy Ronald , Rosenwald Andreas , Enard Wolfgang , Zimber-Strobl Ursula , von Bergwelt-Baildon Michael , Hiddemann Wolfgang , Klapper Wolfram , Schmidt-Supprian Marc , Rudelius Martina , Bararia Deepak , Passerini Verena , Weigert Oliver 
Published: July 2022

AbstractThe variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.
Reproducible measurable residual disease detection by multiparametric flow cytometry in acute myeloid leukemia
Authors: Röhnert Maximilian A. , Kramer Michael , Schadt Jonas , Ensel Philipp , Thiede Christian , Krause Stefan W. , Bücklein Veit , Hoffmann Jörg , Jaramillo Sonia , Schlenk Richard F. , Röllig Christoph , Bornhäuser Martin , McCarthy Nicholas , Freeman Sylvie , Oelschlägel Uta , von Bonin Malte 
Published: July 2022

AbstractMeasurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRDpospatients (HR 3.8,p = 0.006). Overall survival of MRDnegnon-responders was comparable to MRDnegresponders. The inter-rater-reliability for MRD detection was high with a Krippendorffs α of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31 minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.
Glutamine addiction promotes glucose oxidation in triple-negative breast cancer
Authors: Quek Lake-Ee , van Geldermalsen Michelle , Guan Yi Fang , Wahi Kanu , Mayoh Chelsea , Balaban Seher , Pang Angel , Wang Qian , Cowley Mark J. , Brown Kristin K. , Turner Nigel , Hoy Andrew J. , Holst Jeff 
Published: July 2022

AbstractGlutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies.
NNMT promotes the progression of intrahepatic cholangiocarcinoma by regulating aerobic glycolysis via the EGFR-STAT3 axis
Authors: Lu Shounan , Ke Shanjia , Wang Chaoqun , Xu Yanan , Li Zihao , Song Keda , Bai Miaoyu , Zhou Menghua , Yu Hongjun , Yin Bing , Li Xinglong , Feng Zhigang , Hua Yongliang , Pan Shangha , Jiang Hongchi , Li Linqiang , Wu Yaohua , Ma Yong 
Published: July 2022

AbstractNicotinamide N-methyltransferase (NNMT), a member of the N-methyltransferase family, plays an important role in tumorigenesis. However, its expression and biological functions in intrahepatic cholangiocarcinoma (iCCA) remain to be established. In our study, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression. High NNMT expression in iCCA tissues was identified using western blotting and immunohistochemistry (IHC). We identified a significantly higher NNMT expression level in human iCCA tissues than that in adjacent normal tissues. Increased NNMT expression promoted iCCA cell proliferation and metastasis in vitro and in vivo. Mechanistically, NNMT inhibited the level of histone methylation in iCCA cells by consuming the methyl donor S-adenosyl methionine (SAM), thereby promoting the expression of epidermal growth factor receptor (EGFR). EGFR may activate the aerobic glycolysis pathway in iCCA cells by activating the STAT3 signaling pathway. In conclusion, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression.
ANGPTL8 is a negative regulator in pathological cardiac hypertrophy
Authors: Hu Lin , Wei Jiarui , Zhang Yue , Wang Ziyuan , Tang Junming , Tang Jian , Gao Yujiu , Zhang Xiaoqiao , Li Yifan , Liu Yantong , Ma Shinan , Guo Xingrong , Zhang Qiufang 
Published: July 2022

AbstractPathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.
JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability
Authors: Chowdhury Md Al Nayem , Wang Shih-Wei , Suen Ching-Shu , Hwang Ming-Jing , Hsueh Yi-An , Shieh Sheau-Yann 
Published: July 2022

AbstractCheckpoint kinase 2 (CHK2) plays an important role in safeguarding the mitotic progression, specifically the spindle assembly, though the mechanism of regulation remains poorly understood. Here, we identified a novel mitotic phosphorylation site on CHK2 Tyr156, and its responsible kinase JAK2. Expression of a phospho-deficient mutant CHK2 Y156F or treatment with JAK2 inhibitor IV compromised mitotic spindle assembly, leading to genome instability. In contrast, a phospho-mimicking mutant CHK2 Y156E restored mitotic normalcy in JAK2-inhibited cells. Mechanistically, we show that this phosphorylation is required for CHK2 interaction with and phosphorylation of the spindle assembly checkpoint (SAC) kinase Mps1, and failure of which results in impaired Mps1 kinetochore localization and defective SAC. Concordantly, analysis of clinical cancer datasets revealed that deletion of JAK2 is associated with increased genome alteration; and alteration in CHEK2 and JAK2 is linked to preferential deletion or amplification of cancer-related genes. Thus, our findings not only reveal a novel JAK2-CHK2 signaling axis that maintains genome integrity through SAC but also highlight the potential impact on genomic stability with clinical JAK2 inhibition.
The role of N6-methyladenosine-modified non-coding RNAs in the pathological process of human cancer
Authors: Luo Lin , Zhen Yingwei , Peng Dazhao , Wei Cheng , Zhang Xiaoyang , Liu Xianzhi , Han Lei , Zhang Zhenyu 
Published: July 2022

AbstractNon-coding RNAs (ncRNAs) account for the majority of the widespread transcripts of mammalian genomes. They rarely encode proteins and peptides, but their regulatory role is crucial in numerous physiological and pathological processes. The m6A (N6-methyladenosine) modification is one of the most common internal RNA modifications in eukaryotes and is associated with all aspects of RNA metabolism. Accumulating researches have indicated a close association between m6A modification and ncRNAs, and suggested m6A-modified ncRNAs played a crucial role in tumor progression. The correlation between m6A modification and ncRNAs offers a novel perspective for investigating the potential mechanisms of cancer pathological processes, which suggests that both m6A modification and ncRNAs are critical prognostic markers and therapeutic targets in numerous malignancies. In the present report, we summarized the interaction between m6A modification and ncRNA, emphasizing how their interaction regulates pathological processes in cancer.
Orexin neurons inhibit sleep to promote arousal
Authors: De Luca Roberto , Nardone Stefano , Grace Kevin P. , Venner Anne , Cristofolini Michela , Bandaru Sathyajit S. , Sohn Lauren T. , Kong Dong , Mochizuki Takatoshi , Viberti Bianca , Zhu Lin , Zito Antonino , Scammell Thomas E. , Saper Clifford B. , Lowell Bradford B. , Fuller Patrick M. , Arrigoni Elda 
Published: July 2022

AbstractHumans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.
N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis
Authors: Ma Xiaojie , Cao Jie , Zhou Ziyu , Lu Yunkun , Li Qin , Jin Yan , Chen Guo , Wang Weiyun , Ge Wenyan , Chen Xi , Hu Zhensheng , Shu Xiao , Deng Qian , Pu Jiaqi , Liang Chengzhen , Fu Junfen , Liu Jianzhao , Zhu Saiyong 
Published: July 2022

AbstractPancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.
People infer communicative action through an expectation for efficient communication
Authors: Royka Amanda , Chen Annie , Aboody Rosie , Huanca Tomas , Jara-Ettinger Julian 
Published: July 2022

AbstractHumans often communicate using body movements like winks, waves, and nods. However, it is unclear how we identify when someone’s physical actions are communicative. Given people’s propensity to interpret each other’s behavior as aimed to produce changes in the world, we hypothesize that people expect communicative actions to efficiently reveal that they lack an external goal. Using computational models of goal inference, we predict that movements that are unlikely to be produced when acting towards the world and, in particular, repetitive ought to be seen as communicative. We find support for our account across a variety of paradigms, including graded acceptability tasks, forced-choice tasks, indirect prompts, and open-ended explanation tasks, in both market-integrated and non-market-integrated communities. Our work shows that the recognition of communicative action is grounded in an inferential process that stems from fundamental computations shared across different forms of action interpretation.
In situ atomic-scale observation of dislocation climb and grain boundary evolution in nanostructured metal
Authors: Chu Shufen , Liu Pan , Zhang Yin , Wang Xiaodong , Song Shuangxi , Zhu Ting , Zhang Ze , Han Xiaodong , Sun Baode , Chen Mingwei 
Published: July 2022

AbstractNon-conservative dislocation climb plays a unique role in the plastic deformation and creep of crystalline materials. Nevertheless, the underlying atomic-scale mechanisms of dislocation climb have not been explored by direct experimental observations. Here, we report atomic-scale observations of grain boundary (GB) dislocation climb in nanostructured Au during in situ straining at room temperature. The climb of a edge dislocation is found to occur by stress-induced reconstruction of two neighboring atomic columns at the edge of an extra half atomic plane in the dislocation core. This is different from the conventional belief of dislocation climb by destruction or construction of a single atomic column at the dislocation core. The atomic route of the dislocation climb we proposed is demonstrated to be energetically favorable by Monte Carlo simulations. Our in situ observations also reveal GB evolution through dislocation climb at room temperature, which suggests a means of controlling microstructures and properties of nanostructured metals.
Efficient use of cement and concrete to reduce reliance on supply-side technologies for net-zero emissions
Authors: Watari Takuma , Cao Zhi , Hata Sho , Nansai Keisuke 
Published: July 2022

AbstractDecarbonization strategies for the cement and concrete sector have relied heavily on supply-side technologies, including carbon capture and storage (CCS), masking opportunities for demand-side intervention. Here we show that cross-cutting strategies involving both the supply and demand sides can achieve net-zero emissions by 2050 across the entire Japanese cement and concrete cycle without resorting to mass deployment of CCS. Our analysis shows that a series of mitigation efforts on the supply side can reduce 2050 CO2 emissions by up to 80% from baseline levels and that the remaining 20% mitigation gap can be fully bridged by the efficient use of cement and concrete in the built environment. However, this decarbonization pathway is dependent on how CO2 uptake by carbonation and carbon capture and utilization is accounted for in the inventory. Our analysis underscores the importance of including demand-side interventions at the heart of decarbonization strategies and highlights the urgent need to discuss how to account for CO2 uptake in national inventories under the Paris Agreement.
Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children
Authors: Chan Jo-Anne , Loughland Jessica R. , de la Parte Lauren , Okano Satomi , Ssewanyana Isaac , Nalubega Mayimuna , Nankya Felistas , Musinguzi Kenneth , Rek John , Arinaitwe Emmanuel , Tipping Peta , Bourke Peter , Andrew Dean , Dooley Nicholas , SheelaNair Arya , Wines Bruce D. , Hogarth P. Mark , Beeson James G. , Greenhouse Bryan , Dorsey Grant , Kamya Moses , Hartel Gunter , Minigo Gabriela , Feeney Margaret , Jagannathan Prasanna , Boyle Michelle J. 
Published: July 2022

AbstractT-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.
Low-defect-density WS2 by hydroxide vapor phase deposition
Authors: Wan Yi , Li En , Yu Zhihao , Huang Jing-Kai , Li Ming-Yang , Chou Ang-Sheng , Lee Yi-Te , Lee Chien-Ju , Hsu Hung-Chang , Zhan Qin , Aljarb Areej , Fu Jui-Han , Chiu Shao-Pin , Wang Xinran , Lin Juhn-Jong , Chiu Ya-Ping , Chang Wen-Hao , Wang Han , Shi Yumeng , Lin Nian , Cheng Yingchun , Tung Vincent , Li Lain-Jong 
Published: July 2022

AbstractTwo-dimensional (2D) semiconducting monolayers such as transition metal dichalcogenides (TMDs) are promising channel materials to extend Moore’s Law in advanced electronics. Synthetic TMD layers from chemical vapor deposition (CVD) are scalable for fabrication but notorious for their high defect densities. Therefore, innovative endeavors on growth reaction to enhance their quality are urgently needed. Here, we report that the hydroxide W species, an extremely pure vapor phase metal precursor form, is very efficient for sulfurization, leading to about one order of magnitude lower defect density compared to those from conventional CVD methods. The field-effect transistor (FET) devices based on the proposed growth reach a peak electron mobility ~200 cm2/Vs (~800 cm2/Vs) at room temperature (15 K), comparable to those from exfoliated flakes. The FET device with a channel length of 100 nm displays a high on-state current of ~400 µA/µm, encouraging the industrialization of 2D materials.
Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults
Authors: Kared Hassen , Wolf Asia-Sophia , Alirezaylavasani Amin , Ravussin Anthony , Solum Guri , Tran Trung The , Lund-Johansen Fridtjof , Vaage John Torgils , Nissen-Meyer Lise Sofie , Nygaard Unni C. , Hungnes Olav , Robertson Anna H. , Næss Lisbeth Meyer , Trogstad Lill , Magnus Per , Munthe Ludvig A. , Mjaaland Siri 
Published: July 2022

AbstractThe SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.