bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk SNP-induced lncRNA-SLCC1 drives colorectal cancer through activating glycolysis signaling
Authors: Yan Tingting , Shen Chaoqin , Jiang Penglei , Yu Chenyang , Guo Fangfang , Tian Xianglong , Zhu Xiaoqiang , Lu Shiyuan , Han Bingshe , Zhong Ming , Chen Jinxian , Liu Qiang , Chen Yingxuan , Zhang Junfang , Hong Jie , Chen Haoyan , Fang Jing-Yuan 
Published: February 2021

AbstractLong non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens
Authors: Khushman Moh’d , Patel Girijesh Kumar , Maharjan Anu Singh , McMillin Gwendolyn A. , Nelson Cindy , Hosein Peter , Singh Ajay P. 
Published: February 2021

Abstract
Introduction
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20–30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.

Methods
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher’s exact test was used for statistical analysis.

Results
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3–4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3–4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3–4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3–4 FrAEs (p = 0.1108).

Conclusion
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
A systematic review of childhood maltreatment and DNA methylation: candidate gene and epigenome-wide approaches
Authors: Parade Stephanie H. , Huffhines Lindsay , Daniels Teresa E. , Stroud Laura R. , Nugent Nicole R. , Tyrka Audrey R. 
Published: February 2021

AbstractChildhood maltreatment is a major risk factor for chronic and severe mental and physical health problems across the lifespan. Increasing evidence supports the hypothesis that maltreatment is associated with epigenetic changes that may subsequently serve as mechanisms of disease. The current review uses a systematic approach to identify and summarize the literature related to childhood maltreatment and alterations in DNA methylation in humans. A total of 100 empirical articles were identified in our systematic review of research published prior to or during March 2020, including studies that focused on candidate genes and studies that leveraged epigenome-wide data in both children and adults. Themes arising from the literature, including consistent and inconsistent patterns of results, are presented. Several directions for future research, including important methodological considerations for future study design, are discussed. Taken together, the literature on childhood maltreatment and DNA methylation underscores the complexity of transactions between the environment and biology across development.
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness
Authors: Bonneau Marion , Sullivan Shane T. O’ , Gonzalez-Lozano Miguel A. , Baxter Paul , Gautier Phillippe , Marchisella Elena , Hardingham Neil R. , Chesters Robert A. , Torrance Helen , Howard David M. , Jansen Maurits A. , McMillan Melanie , Singh Yasmin , Didier Michel , Koopmans Frank , Semple Colin A. , McIntosh Andrew M. , Volkmer Hansjürgen , Loos Maarten , Fox Kevin , Hardingham Giles E. , Vernon Anthony C. , Porteous David J. , Smit August B. , Price David J. , Kirsty Millar J. 
Published: February 2021

AbstractA balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.
A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models
Authors: Morimoto Yoshiro , Ono Shinji , Yoshida Shintaro , Mishima Hiroyuki , Kinoshita Akira , Tanaka Takeshi , Komohara Yoshihiro , Kurotaki Naohiro , Kishino Tatsuya , Okazaki Yuji , Ozawa Hiroki , Yoshiura Koh-ichiro , Imamura Akira 
Published: February 2021

AbstractGenetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12:132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.
Key chemokines direct migration of immune cells in solid tumors
Authors: Kohli Karan , Pillarisetty Venu G. , Kim Teresa S. 
Published: February 2021

AbstractImmune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.
Zinc transporter ZIP7 is a novel determinant of ferroptosis
Authors: Chen Po-Han , Wu Jianli , Xu Yitong , Ding Chien-Kuang Cornelia , Mestre Alexander A. , Lin Chao-Chieh , Yang Wen-Hsuan , Chi Jen-Tsan 
Published: February 2021

AbstractFerroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.
GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway
Authors: Yu Xiaoting , Jin Jing , Zheng Yanwen , Zhu Hua , Xu Hui , Ma Jun , Lan Qing , Zhuang Zhixiang , Chen Clark C. , Li Ming 
Published: February 2021

AbstractGuanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.
Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma
Authors: Chen Xiaopeng , Cheng Bin , Dai Dafei , Wu Yuhai , Feng Zhiwen , Tong Chaogang , Wang Xiangming , Zhao Jun 
Published: February 2021

AbstractHeparanase (HPSE) is a kind of multifunctional extracellular hydrolase, and related to metastasis of hepatocellular carcinoma (HCC). Endothelial necroptosis promotes the metastasis of cancer cells. It is not clear whether HPSE could mediate necroptosis of microvascular endothelial cells (MVECs) to promote HCC metastasis. Here we found HPSE expression was up-regulated in HCC tissues and its over-expression was correlated with multiple tumor foci, microvascular invasion, and poor outcome of HCC patients. Non-contact co-culture experiments showed high-expressed HPSE in HCC cells mediated the necroptosis of human umbilical vein endothelial cells (HUVECs) and elevated the expression levels of syndecan-1 (SDC-1) and tumor necrosis factor-α (TNF-α) in vitro. As a result of necroptosis, trans-endothelial migration (TEM) of HCC cells was increased. Conversely, both HPSE and SDC-1 knockdowns reversed necroptosis and decreased TNF-α expression level, while HPSE over-expression increased SDC-1 and TNF-α expression and aggravated necroptosis. Animal experiments found that the nude mice, intraperitoneally injected with HPSE high expressing HCC cells, had obvious necroptosis of MVECs and high intrahepatic metastasis rate, which could be relieved by inhibitor of necroptosis. Morever, HPSE elevated the expression levels of p38 mitogen-activated protein kinase (p38 MAPK) rather than nuclear factor kappa B in vitro. Our data suggest that HPSE induces necroptosis of MVECs to promote the metastasis of HCC by activating HPSE/SDC-1/TNF-α axis and p38 MAPK pathway.
Smac-mimetics reduce numbers and viability of human osteoclasts
Authors: Moen Ingrid Nyhus , Westhrin Marita , Håland Erling , Haug Markus , Nonstad Unni , Klaharn Merisa , Standal Therese , Starheim Kristian K. 
Published: February 2021

AbstractElevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis. In this manuscript, we show that the two SM birinapant and LCL-161 reduced the number and viability of primary human OC, and induced TNF-dependent cell death in OC precursors (pre-OC). Birinapant was more cytotoxic than LCL-161 and induced predominantly apoptosis and to some degree necroptosis. Both inhibitors restrained osteoclastogenesis induced by myeloma patient bone-marrow aspirates. SM has gained attention as novel treatment strategies both for cancer and chronic inflammatory pathologies, but limited information has been available on interactions with primary human immune cells. As LCL-161 is in phase 2 clinical studies for multiple myeloma, we propose that SM might possess additional benefits in reducing bone degradation in myeloma patients. Taken together, we show that SM reduces human osteoclastogenesis, and that these compounds may represent promising drug candidates for pathological bone degradation.
Diatom fucan polysaccharide precipitates carbon during algal blooms
Authors: Vidal-Melgosa Silvia , Sichert Andreas , Francis T. Ben , Bartosik Daniel , Niggemann Jutta , Wichels Antje , Willats William G. T. , Fuchs Bernhard M. , Teeling Hanno , Becher Dörte , Schweder Thomas , Amann Rudolf , Hehemann Jan-Hendrik 
Published: February 2021

AbstractThe formation of sinking particles in the ocean, which promote carbon sequestration into deeper water and sediments, involves algal polysaccharides acting as an adhesive, binding together molecules, cells and minerals. These as yet unidentified adhesive polysaccharides must resist degradation by bacterial enzymes or else they dissolve and particles disassemble before exporting carbon. Here, using monoclonal antibodies as analytical tools, we trace the abundance of 27 polysaccharide epitopes in dissolved and particulate organic matter during a series of diatom blooms in the North Sea, and discover a fucose-containing sulphated polysaccharide (FCSP) that resists enzymatic degradation, accumulates and aggregates. Previously only known as a macroalgal polysaccharide, we find FCSP to be secreted by several globally abundant diatom species including the genera Chaetoceros and Thalassiosira. These findings provide evidence for a novel polysaccharide candidate to contribute to carbon sequestration in the ocean.
Robust inference of kinase activity using functional networks
Authors: Yılmaz Serhan , Ayati Marzieh , Schlatzer Daniela , Çiçek A. Ercüment , Chance Mark R. , Koyutürk Mehmet 
Published: February 2021

AbstractMass spectrometry enables high-throughput screening of phosphoproteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer’s disease and Parkinson’s disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool at http://rokai.io.
GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression
Authors: Wu Yeda , Murray Graham K. , Byrne Enda M. , Sidorenko Julia , Visscher Peter M. , Wray Naomi R. 
Published: February 2021

AbstractGenetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genesMUC1,MUC6, FUT2,PSCA,ABO,CDX2, GASTandCCKBR. There are previously established roles in susceptibility toHelicobacter pyloriinfection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
A high throughput optical method for studying compositional effects in electrocatalysts for CO2 reduction
Authors: Hitt Jeremy L. , Li Yuguang C. , Tao Songsheng , Yan Zhifei , Gao Yue , Billinge Simon J. L. , Mallouk Thomas E. 
Published: February 2021

AbstractIn the problem of electrochemical CO2 reduction, the discovery of earth-abundant, efficient, and selective catalysts is essential to enabling technology that can contribute to a carbon-neutral energy cycle. In this study, we adapt an optical high throughput screening method to study multi-metallic catalysts for CO2 electroreduction. We demonstrate the utility of the method by constructing catalytic activity maps of different alloyed elements and use X-ray scattering analysis by the atomic pair distribution function (PDF) method to gain insight into the structures of the most active compositions. Among combinations of four elements (Au, Ag, Cu, Zn), Au6Ag2Cu2 and Au4Zn3Cu3 were identified as the most active compositions in their respective ternaries. These ternary electrocatalysts were more active than any binary combination, and a ca. 5-fold increase in current density at potentials of −0.4 to −0.8 V vs. RHE was obtained for the best ternary catalysts relative to Au prepared by the same method. Tafel plots of electrochemical data for CO2 reduction and hydrogen evolution indicate that the ternary catalysts, despite their higher surface area, are poorer catalysts for the hydrogen evolution reaction than pure Au. This results in high Faradaic efficiency for CO2 reduction to CO.
Moiré pattern of interference dislocations in condensate of indirect excitons
Authors: Leonard J. R. , Hu Lunhui , High A. A. , Hammack A. T. , Wu Congjun , Butov L. V. , Campman K. L. , Gossard A. C. 
Published: February 2021

AbstractInterference patterns provide direct measurement of coherent propagation of matter waves in quantum systems. Superfluidity in Bose–Einstein condensates of excitons can enable long-range ballistic exciton propagation and can lead to emerging long-scale interference patterns. Indirect excitons (IXs) are formed by electrons and holes in separated layers. The theory predicts that the reduced IX recombination enables IX superfluid propagation over macroscopic distances. Here, we present dislocation-like phase singularities in interference patterns produced by condensate of IXs. We analyze how exciton vortices and skyrmions should appear in the interference experiments and show that the observed interference dislocations are not associated with these phase defects. We show that the observed interference dislocations originate from the moiré effect in combined interference patterns of propagating condensate matter waves. The interference dislocations are formed by the IX matter waves ballistically propagating over macroscopic distances. The long-range ballistic IX propagation is the evidence for IX condensate superfluidity.