bluuebunny/crossref_metadata_2025_split huggingface dataset:
The methylation ofSDC2andTFPI2defined three methylator phenotypes of colorectal cancer
Authors: Lei Ruixue , Zhao Yanteng , Huang Kai , Wan Kangkang , Li Tingting , Yang Haijun , Lv Xianping 
Published: March 2021

AbstractMethylation-based noninvasive molecular diagnostics are easy and feasible tools for the early detection of colorectal cancer (CRC). However, many of them have the limitation of low sensitivity with some CRCs detection failed in clinical practice. In this study, the clinical and pathological characteristics, as well as molecular features of three methylator-groups, defined by the promoter methylation status ofSDC2andTFPI2, were investigated in order to improve the performance of CRC detection. The Illumina Infinium 450k Human DNA methylation data and clinical information of CRCs were collected from The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO) database. CRC samples were divided into three groups, HH (dual-positive), HL (single positive) and LL (dual-negative) according to the methylation status ofSDC2andTFPI2promoters. Differences in age, tumor location, microsatellite instable status and differentially expressed genes (DEGs) were evaluated among the three groups and these findings were then confirmed in our inner CRC dataset. The combination of methylatedSDC2andTFPI2showed a superior performance of distinguishing CRCs from normal controls than each alone. Samples of HL group were more often originated from left-side CRCs whereas very few of them were from right-side (P< 0.05). HH grouped CRCs showed a higher level of microsatellite instability and mutation load than other two groups (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02,P= 0.0055). All mutations ofBRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were found in HH group (HH/HL/LL: 51/0/0,P= 0.018). Also there was a significantly older patient age at the diagnosis in HH group. Gene expression analysis identified 37, 84 and 22 group-specific DEGs for HH, HL and LL, respectively. Functional enrichment analysis suggested that HH specific DEGs were mainly related to the regulation of transcription and other processes, while LL specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration. The three defined mathylator groups showed great difference in tumor location, patient age, MSI and ECM biological process, which could facilitate the development of more effective biomarkers for CRC detection.
Integrative multi-omics approach for stratification of tumor recurrence risk groups of Hepatocellular Carcinoma patients
Authors: Kaur Harpreet , Lathwal Anjali , Raghava Gajendra P.S. 
Published: March 2021

AbstractPostoperative tumor recurrence is one of the major concerns associated with the poor prognosis of HCC patients. There is yet to elucidate a standard surveillance system for HCC recurrence risk owing to complexity of this malignancy. Generation of multi-omics data from patients facilitate the identification of robust signatures for various diseases. Thus, the current study is an attempt to develop the prognostic models employing multi-omics data to significantly (p-value <0.05) stratify the recurrence high-risk (median Recurrence Free Survival time (RFS) =<12 months) and low-risk groups (median RFS >12 months). First, we identified key 90RNA, 50miRNA and 50 methylation features and developed prognostic models; attained reasonable performance (C-Index >0.70, HR >2.5), on training and validation datasets. Subsequently, we developed a prognostic (PI) model by integrating the four multi-omics features (SUZ12, hsa-mir-3936, cg18465072, and cg22852503), that are biologically inter-linked with each other. This model achieved reasonable performance on training and validation dataset, i.e. C-Index 0.72, HR of 2.37 (1.61 - 3.50), p-value of 6.72E-06, Brier score 0.19 on training dataset, and C-Index 0.72 (95% CI: 0.63 - 0.80), HR of 2.37 (95% CI: 1.61 - 3.50), p-value of 0.015, Brier score 0.19 on validation dataset. Eventually, Drugbank data was investigated to elucidate therapeutic potential of these signatures. We have identified nine potential drugs against three genes (CA9, IL1A, KCNJ15) that are positively correlated with the tumor recurrence. We anticipate these results from our study will help researchers and clinicians to improve the HCC recurrence surveillance, eventually outcome of patients.
Preparation of functional IgY that potently neutralizes HIV-1 in TZM-bl Cell line
Authors: Wei Jinchen , Zhang Yanqun , Zeng Yonglian , Yang Yang , Liang Ronggan , Liang Chengqin , Dai Zhigang , He Songqing , Wu Shuwen , Xu Qing 
Published: March 2021

ABSTRACTAIDS caused by HIV is one of the most serious public health challenges in the world. As we all know, Antiretroviral therapy (ART) is the most effective way to treat AIDS so far, however, forthe reasons of drug resistance, side effects, compliance, economy, limited its using widely. On the other hand, AIDS cannot be completely cured by ART. While the characterization of bnAbs (broadly neutralizing antibodies) in potent HIV neutralization provides considerable insight into HIV curing, it also can be used for passive immunotherapy or combination with ART for HIV-1 treatment. Here we report a novel technology to produce an neutralized activity bnAbs named HIV-1-IgY, which was extracted from the immunized Chicken egg by pNL4-3 virus antigens, and further purified using Water dilution and Salting out method. The specificity, titer and neutralizing activity of HIV-1-IgY was analyzed by Western blotting, ELISA and TZM-bl cell line evaluation system respectively. The results showed that theHIV-1-IgY has high neutralized activity to HIV in vitro; nearly 90% of HIV-1 were neutralized at 1.89μM in TZM-blsystem, which indicated that IgY may be a source of antibodies for AIDS prevention and treatment. Despite its needs to further consider and evaluate neutralized activity in-vivo and the potential mechanisms, Our data showed that we obtained an HIV-1-IgY which could effectively neutralize HIV-l IIIB virus in vitro.
Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma
Authors: Jang Hee-Jin , Truong Cynthia Y. , Lo Eric M. , Holmes Hudson M. , Ramos Daniela , Ramineni Maheshwari , Lee Ju-Seog , Wang Daniel Y. , Pietropaolo Massimo , Ripley R Taylor , Burt Bryan M. , Lee Hyun-Sung 
Published: March 2021

ABSTRACTBackgroundDespite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.MethodsWe generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.ResultsImmunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion ofCDKN2Awas highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome byCDK4/6inhibition, we tested whetherCDK4/6inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived fromCdkn2a(−/−)AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration ofCDK4/6inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 orCDK4/6inhibitor alone.ConclusionsWe identified a novel therapeutic target,CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials ofCDK4/6inhibitors in the more than 40% of patients with MPM who demonstrate loss ofCDKN2A.
Inhibiting SARS-CoV-2 infectionin vitroby suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal
Authors: Tanimoto Keiji , Hirota Kiichi , Fukazawa Takahiro , Matsuo Yoshiyuki , Nomura Toshihito , Tanuza Nazmul , Hirohashi Nobuyuki , Bono Hidemasa , Sakaguchi Takemasa 
Published: March 2021

AbstractSince understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects onACE2might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressedACE2expression in a dose-dependent manner along with inducingCYP1A1. Knock-down experiments indicated a reduction ofACE2by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including CSE, FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.
Focal Laser Stimulation of Fly Nociceptors Activates Distinct Axonal and Dendritic Ca2+Signals
Authors: Basak Rajshekhar , Sutradhar Sabyasachi , Howard Jonathon 
Published: March 2021

AbstractDrosophilaClass IV neurons are polymodal nociceptors that detect noxious mechanical, thermal, optical and chemical stimuli. Escape behaviors in response to attacks by parasitoid wasps are dependent on Class IV cells, whose highly branched dendritic arbors form a fine meshwork that is thought to enable detection of the wasp’s needle-like ovipositor barb. To understand how mechanical stimuli trigger cellular responses, we used a focused 405-nm laser to create highly local lesions to probe the precise position needed in evoke responses. By imaging calcium signals in dendrites, axons, and soma in response to stimuli of varying positions, intensities and spatial profiles, we discovered that there are two distinct nociceptive pathways. Direct stimulation to dendrites (the contact pathway) produces calcium responses in axons, dendrites and the cell body whereas stimulation adjacent to the dendrite (the non-contact pathway) produces calcium responses in the axons only. We interpret the non-contact pathway as damage to adjacent cells releasing diffusible molecules that act on the dendrites. Axonal responses have higher sensitivities and shorter latencies. In contrast, dendritic responses have lower sensitivities and longer latencies. Stimulation of finer, distal dendrites leads to smaller responses than stimulation of coarser, proximal dendrites, as expected if the contact response depends on the geometric overlap of the laser profile and the dendrite diameter. Because the axon signals to the CNS to trigger escape behaviors, we propose that the density of the dendritic meshwork is high not only to enable direct contact with the ovipositor, but also to enable neuronal activation via diffusing signals from damaged surrounding cells. Dendritic contact evokes responses throughout the dendritic arbor, even to regions distant and distal from the stimulus. These dendrite-wide calcium signals may facilitate hyperalgesia or cellular morphological changes following dendritic damage.Statement of SignificanceAnimals encounter a wide range of noxious stimuli in the natural world. Nociceptive neurons are specialized cells that sense harmful stimuli and trigger avoidance responses. Class IV cells, located under the cuticle inDrosophilalarvae, are polymodal nociceptors that respond to noxious mechanical, thermal, optical, and chemical stimuli. To investigate the spatial requirements of mechanoreception in Class IV neurons, we measured calcium signals evoked by a focused laser beam that creates highly localized tissue damage. We discovered that different cellular compartments – axons and dendrites – responded differentially depending on whether the stimulus makes direct contact with the neuron or not. This provides evidence that mechanical nociception in Class IV cells occurs via two distinct pathways.
Locus specific epigenetic modalities of random allelic expression imbalance
Authors: Marion-Poll Lucile , Forêt Benjamin , Zielinski Dina , Massip Florian , Attia Mikael , Carter Ava C , Syx Laurène , Chang Howard Y , Gendrel Anne-Valerie , Heard Edith 
Published: March 2021

ABSTRACTMost autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression was not observed in ESCs, but when we assessed expression status in more than 200 clones of neuronal progenitor cells, we observed high frequencies of monoallelism. We uncovered unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up novel therapeutic perspectives.
Universal gene co-expression network reveals receptor-like protein genes conferring broad-spectrum resistance in pepper (Capsicum annuumL.)
Authors: Kang Won-Hee , Lee Junesung , Koo Namjin , Kwon Ji-Su , Park Boseul , Kim Yong-Min , Yeom Seon-In 
Published: March 2021

ABSTRACTReceptor-like proteins (RLPs) on the plant cell surface have been implicated in immune responses and developmental processes. Although hundreds ofRLPgenes have been identified in plants, only a few RLPs have been functionally characterized in a limited number of plant species. Here, we identifiedRLPsin the pepper (Capsicum annuum) genome, and performed comparative transcriptomics coupled with the analysis of conserved gene co-expression networks (GCNs) to reveal the role of core RLP regulators in pepper–pathogen interactions. A total of 102 RNA-seq datasets of pepper plants infected with four pathogens were used to construct CaRLP-targeted GCNs (CaRLP-GCN). All resistance-responsive CaRLP-GCNs were merged to construct a universal GCN. Fourteen hubCaRLPs, tightly connected with defense related gene clusters, were identified in eight modules. Based on the CaRLP-GCNs, we experimentally tested whether hubCaRLPsin the universal GCN are involved in biotic stress response. Of the nine hubCaRLPstested by virus-induced gene silencing (VIGS), three genes (CaRLP264,CaRLP277, andCaRLP351) showed defense suppression with less hypersensitive response (HR)-like cell death in race-specific and non-host resistance response to viruses and bacteria, respectively, and consistently enhanced susceptibility toRalstonia solanacearumand/orPhytophthora capsici. These data suggest that keyCaRLPsexhibit conserved functions in response to multiple biotic stresses and can be used for engineering of a plant with broad-spectrum resistance. Altogether, we show that generation of a universal GCN using comprehensive transcriptome datasets could provide important clues for uncovering genes involved in various biological processes.
The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of Acute Myeloid Leukemias
Authors: Rosa Paolillo , Mathias Boulanger , Pierre Gâtel , Ludovic Gabellier , Denis Tempé , Rawan Hallal , Marion De Toledo , Jérome Moreaux , Hayeon Baik , Gueret Elise , Christian Récher , Jean-Emmanuel Sarry , Guillaume Cartron , Marc Piechaczyk , Guillaume Bossis 
Published: March 2021

AbstractResistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB,CYBA,NCF1,NCF2,NCF4andRAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox(CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0-M2 ones. Using a gene expression-based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic-based risk classification, in AML patients.
The genetics of gene expression in aC. elegansmulti parental recombinant inbred line population
Authors: Snoek Basten L. , Sterken Mark G. , Nijveen Harm , Volkers Rita J.M. , Riksen Joost , Rosenstiel Philip C. , Schulenburg Hinrich , Kammenga Jan E. 
Published: March 2021

AbstractStudying genetic variation of gene expression provides a powerful way to unravel the molecular components underlying complex traits. Expression QTL studies have been performed in several different model species, yet most of these linkage studies have been based on genetic segregation of two parental alleles. Recently we developed a multi-parental segregating population of 200 recombinant inbred lines (mpRILs) derived from four wild isolates (JU1511, JU1926, JU1931 and JU1941) in the nematodeCaenorhabditis elegans. We used RNA-seq to investigate how multiple alleles affect gene expression in these mpRILs. We found 1,789 genes differentially expressed between the parental lines. Transgression, expression beyond any of the parental lines in the mpRILs, was found for 7,896 genes. For expression QTL mapping almost 9,000 SNPs were available. By combining these SNPs and the RNA-seq profiles of the mpRILs, we detected almost 6,800 eQTLs. Mosttrans-eQTLs (63%) co-locate in six newly identifiedtrans-bands. Thetrans-eQTLs found in previous 2-parental allele eQTL experiments and this study showed some overlap (17.5%- 46.8%), highlighting on the one hand that a large group of genes is affected by polymorphic regulators across populations and conditions, on the other hand it shows that the mpRIL population allows identification of novel gene expression regulatory loci. Taken together, the analysis of our mpRIL population provides a more refined insight intoC. eleganscomplex trait genetics and eQTLs in general, as well as a starting point to further test and develop advanced statistical models for detection of multi-allelic eQTLs and systems genetics studying the genotype-phenotype relationship.
Genotyping-by-sequencing-based identification ofArabidopsispattern recognition receptor RLP32 recognizing proteobacterial translation initiation factor IF1
Authors: Fan Li , Fröhlich Katja , Melzer Eric , Albert Isabell , Pruitt Rory N. , Zhang Lisha , Albert Markus , Kim Sang-Tae , Chae Eunyoung , Weigel Detlef , Gust Andrea A. , Nürnberger Thorsten 
Published: March 2021

AbstractPattern-triggered immunity (PTI) is a central component of plant immunity. Activation of PTI relies on the recognition of microbe-derived structures, termed patterns, through plant encoded surface-resident pattern recognition receptors (PRRs). We have identified proteobacterial translation initiation factor 1 (IF1) as an immunogenic pattern that triggers PTI inArabidopsis thalianaand some related Brassicaceae species. Unlike most other immunogenic patterns identified, IF1 elicitor activity cannot be assigned to a small peptide epitope, suggesting that tertiary fold features are required for IF1 receptor activation. We have deployed natural variation in IF1 sensitivity to identify leucine-rich repeat (LRR) receptor-like protein 32 (RLP32) as the correspondingArabidopsisreceptor using a restriction site-associated DNA sequencing (RAD-seq) approach. Transgenic expression of RLP32 confers IF1 sensitivity torlp32mutants, IF1-insensitiveArabidopsisaccessions and IF1-insensitiveNicotiana benthamiana. RLP32 binds IF1 specifically and forms complexes with LRR receptor kinases SOBIR1 and BAK1 to mediate signaling. Similar to previously identified PRRs RLP32 confers resistance toPseudomonas syringaeinfection, highlighting an unexpectedly complex array of bacterial pattern sensors within a single plant species.
SARS-CoV-2 variant with higher affinity to ACE2 shows reduced sera neutralization susceptibility
Authors: Vogel Monique , Chang Xinyue , Sousa Augusto Gilles , Mohsen Mona O. , Speiser Daniel E. , Bachmann Martin F. 
Published: March 2021

AbstractBackgroundSeveral new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein.ObjectiveWe aimed to assess how mutations in the SARS-CoV-2 RBD affect receptor affinity to angiotensin-converting enzyme 2 (ACE2) and neutralization by anti-RBD serum antibodies.MethodsWe produced a SARS-CoV-2 RBD mutant (RBDmut) with key mutations (E484K, K417N, N501Y) from the newly emerged Brazilian variant. Using Biolayer Interferometry, we analyzed the binding of this mutant to ACE2, and the susceptibility to neutralization by sera from vaccinated mice and COVID-19 convalescent patients.ResultsKinetic profiles showed increased RBDmut - ACE2 affinity compared to RBDwt, and binding of vaccine-elicited or convalescent sera was significantly reduced. Likewise, both sera types showed significantly reduced ability to block RBDmut - ACE2 binding indicating that antibodies induced by RBDwt have reduced capability to neutralize mutant virus.ConclusionOur physiochemical data show enhanced infectivity and reduced neutralization by polyclonal antibodies of the Brazilian variant of SARS-CoV-2.Capsule summarySARS-CoV-2 variant with Brazilian RBD mutations shows increased ACE2 affinity and reduced susceptibility to blockage by vaccine-elicited and convalescent sera.