bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor Alpha-Induced Interleukin-1 Alpha Synthesis and Cell Death Is Increased in Mouse Epithelial Cells Infected With Chlamydia muridarum
Authors: Nagarajan Uma M , Cho Crescentia , Gyorke Clare E , Nagarajan Shanmugam , Ezzell J Ashley , Brochu Hayden , Huntress Ian , Harrell Erin , Peng Xinxia 
Published: March 2021

Abstract
Chlamydia trachomatis-genital infection in women can be modeled in mice using Chlamydia muridarum. Using this model, it has been shown that the cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1α lead to irreversible tissue damage in the oviducts. In this study, we investigated the contribution of TNFα on IL-1α synthesis in infected epithelial cells. We show that C muridarum infection enhanced TNFα-induced IL-1α expression and release in a mouse epithelial cell line. In addition to IL-1α, several TNFα-induced inflammatory genes were also highly induced, and infection enhanced TNF-induced cell death. In the mouse model of genital infection, oviducts from mice lacking the TNFα receptor displayed minimal staining for IL-1α compared with wild-type oviducts. Our results suggest TNFα and IL-1α enhance each other’s downstream effects resulting in a hyperinflammatory response to chlamydial infection. We propose that biologics targeting TNF-induced IL-1α synthesis could be used to mitigate tissue damage during chlamydial infection.
In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae
Authors: Ni Wentao , Yang Deqing , Guan Jie , Xi Wen , Zhou Dexun , Zhao Lili , Cui Junchang , Xu Yu , Gao Zhancheng , Liu Youning 
Published: March 2021

Abstract

Objectives
Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies.

Methods
Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time–kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened.

Results
The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time–kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants.

Conclusions
Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.
ZmMs25 encoding a plastid-localized fatty acyl reductase is critical for anther and pollen development in maize
Authors: Zhang Simiao , Wu Suowei , Niu Canfang , Liu Dongcheng , Yan Tingwei , Tian Youhui , Liu Shuangshuang , Xie Ke , Li Ziwen , Wang Yanbo , Zhao Wei , Dong Zhenying , Zhu Taotao , Hou Quancan , Ma Biao , An Xueli , Li Jinping , Wan Xiangyuan 
Published: March 2021

Abstract
Fatty acyl reductases (FARs) catalyse the reduction of fatty acyl-coenzyme A (CoA) or -acyl carrier protein (ACP) substrates to primary fatty alcohols, which play essential roles in lipid metabolism in plants. However, the mechanism by which FARs are involved in male reproduction is poorly defined. Here, we found that two maize allelic mutants, ms25-6065 and ms25-6057, displayed defective anther cuticles, abnormal Ubisch body formation, impaired pollen exine formation and complete male sterility. Based on map-based cloning and CRISPR/Cas9 mutagenesis, Zm00001d048337 was identified as ZmMs25, encoding a plastid-localized FAR with catalytic activities to multiple acyl-CoA substrates in vitro. Four conserved residues (G101, G104, Y327 and K331) of ZmMs25 were critical for its activity. ZmMs25 was predominantly expressed in anther, and was directly regulated by transcription factor ZmMYB84. Lipidomics analysis revealed that ms25 mutation had significant effects on reducing cutin monomers and internal lipids, and altering the composition of cuticular wax in anthers. Moreover, loss of function of ZmMs25 significantly affected the expression of its four paralogous genes and five cloned lipid metabolic male-sterility genes in maize. These data suggest that ZmMs25 is required for anther development and male fertility, indicating its application potential in maize and other crops.
Investigating the theory of propagating fluctuations with numerical models of stochastic accretion discs
Authors: Turner Samuel G D , Reynolds Christopher S 
Published: March 2021

ABSTRACT
Across a large range of scales, accreting sources show remarkably similar patterns of variability, most notably the log-normality of the luminosity distribution and the linear root-mean square (rms)–flux relationship. These results are often explained using the theory of propagating fluctuations in which fluctuations in the viscosity create perturbations in the accretion rate at all radii, propagate inwards, and combine multiplicatively. While this idea has been extensively studied analytically in a linear regime, there has been relatively little numerical work investigating the non-linear behaviour. In this paper, we present a suite of stochastically driven 1D α-disc simulations, exploring the behaviour of these discs. We find that the eponymous propagating fluctuations are present in all simulations across a wide range of model parameters, in contradiction to previous work. Of the model parameters, we find by far the most important to be the time-scale on which the viscosity fluctuations occur. Physically, this time-scale will depend on the underlying physical mechanism, thought to be the magnetorotational instability (MRI). We find a close relationship between this fluctuation time-scale and the break frequency in the power spectral density of the luminosity, a fact which could allow observational probes of the behaviour of the MRI dynamo. We report a fitting formula for the break frequency as a function of the fluctuation time-scale, the disc thickness, and the mass of the central object.
ResistoXplorer: a web-based tool for visual, statistical and exploratory data analysis of resistome data
Authors: Dhariwal Achal , Junges Roger , Chen Tsute , Petersen Fernanda C 
Published: March 2021

Abstract
The study of resistomes using whole metagenomic sequencing enables high-throughput identification of resistance genes in complex microbial communities, such as the human microbiome. Over recent years, sophisticated and diverse pipelines have been established to facilitate raw data processing and annotation. Despite the progress, there are no easy-to-use tools for comprehensive visual, statistical and functional analysis of resistome data. Thus, exploration of the resulting large complex datasets remains a key bottleneck requiring robust computational resources and technical expertise, which creates a significant hurdle for advancements in the field. Here, we introduce ResistoXplorer, a user-friendly tool that integrates recent advancements in statistics and visualization, coupled with extensive functional annotations and phenotype collection, to enable high-throughput analysis of common outputs generated from metagenomic resistome studies. ResistoXplorer contains three modules—the ‘Antimicrobial Resistance Gene Table’ module offers various options for composition profiling, functional profiling and comparative analysis of resistome data; the ‘Integration’ module supports integrative exploratory analysis of resistome and microbiome abundance profiles derived from metagenomic samples; finally, the ‘Antimicrobial Resistance Gene List’ module enables users to intuitively explore the associations between antimicrobial resistance genes and the microbial hosts using network visual analytics to gain biological insights. ResistoXplorer is publicly available at http://www.resistoxplorer.no.
BIMG-11. PHARMACODYNAMIC EVALUATION OF IDH AND EGFR INHIBITION IN HUMAN GLIOMAS USING MOLECULAR MRI
Authors: Ellingson Benjamin , Yao Jingwen , Hagiwara Akifumi , Nathanson David , Oughourlian Talia , Everson Richard , Salamon Noriko , Pope Whitney , Nghiemphu Phioanh , Lai Albert , Liau Linda , Cloughesy Timothy 
Published: March 2021

Abstract
Metabolic differences are inherent to specific glioma subtypes and can be altered using targeted treatments, including IDH and EGFR inhibition. Using a large cohort of patients scanned at UCLA and other centers over the last 5 years, we demonstrate that IDH, 1p19q, and EGFR alterations uniquely contribute to alterations in glycolysis and oxygen utilization using a clinically available molecular MRI technique termed amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI). Our data shows that CEST-SAGE-EPI estimates of tumor acidity are strongly associated with the degree of glycolysis as evaluated with direct pH measurements, quantitative IHC, bioenergetics experiments, and correlations with 18F-FDG PET images. Data further reveals that IDH wild type gliomas have higher acidity and oxygen utilization compared with IDH mutant gliomas, 1p19q non-codeleted gliomas (astrocytomas) have higher tumor acidity compared to 1p19q codeleted gliomas (oligodendrogliomas), and EGFR amplified gliomas have higher oxygen utilization compared with non-amplified gliomas. Additionally, phase II clinical trial data suggests successful IDH inhibition results in an early and measurable increase in tumor acidity and further reduction in oxygen utilization, signifying suppression of oxidative phosphorylation and/or glutaminolysis in favor of glycolysis. Alternatively, phase II clinical trial data suggests successful EGFR inhibition with brain penetrant agents results in early reductions in tumor acidity and 18F-FDG PET uptake, consistent with a reduction in glycolysis. Data also indicates that continual increases in tumor acidity during routine follow-up after initial therapeutic changes results in uniformly worse outcomes in all tumor subtypes under all mentioned treatment scenarios.
BIMG-19. 18F-FLUCICLOVINE PET/CT TO DISTINGUISH RADIATION NECROSIS FROM TUMOR PROGRESSION IN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY: A PROSPECTIVE PILOT STUDY
Authors: Tom Martin 
Published: March 2021

Abstract

PURPOSE
To estimate the accuracy of 18F-Fluciclovine PET/CT in distinguishing radiation necrosis (RN) from tumor progression (TP) among patients with brain metastases (BM) having undergone prior stereotactic radiosurgery (SRS) who presented with a follow-up MRI brain (with DSC-MR perfusion) which was equivocal for RN versus TP.

METHODS
Within 30 days of equivocal MRI brain, subjects underwent 18F-Fluciclovine PET/CT on a Siemens Biograph mCT scanner with a 10 mCi bolus dose immediately prior to PET. Data were collected in list mode for 25 minutes post-injection and were reconstructed as a static image of data 10–25 minutes post-injection, and as a dynamic series of four 5-minute frames between 5–25 minutes post-injection. Quantitative metrics for each lesion were documented including SUVmax, SUVmean, SUVpeak, and normal brain SUVmean. Lesion to normal brain ratios were calculated. The reference standard was clinical follow-up with MRI brain (with DSC-MR perfusion) every 2–4 months until multidisciplinary consensus (or tissue confirmation) for diagnosis of RN versus TP.

RESULTS
From 7/2019-11/2020, 16 of 16 planned subjects enrolled and underwent 18F-Fluciclovine PET/CT for evaluation of 21 brain lesions. Primary histology included NSCLC (n=7), breast (n=5), melanoma (n=3), and endometrial (n=1). Ranges of quantitative metrics were: SUVmax, 2.18–12.1; SUVmean, 1.16–7.37; SUVpeak, 1.06–5.14; normal brain SUVmean, 0.19–0.50; SUVmax/normal ratio, 7.5–45.4; SUVmean/normal ratio, 4.2–26.3; and SUVpeak/normal ratio, 3.9–26.4. Among the patients 10 patients with 12 lesions who completed follow up, estimates of the area under the receiver operating characteristic curve for SUVmax, SUVmean, and SUVpeak were: 0.93, 0.93, and 0.82, respectively.

CONCLUSION
In this population, 18F-Fluciclovine PET/CT favorably produces a wide range of lesion quantitative metric values, low uptake in the normal brain, and promising accuracy to distinguish RN from TP. Completion of follow-up for all patients is required. Phase II and III studies are under development.
DDRE-14. DE-NOVO PURINE BIOSYNTHESIS IS A MAJOR DRIVER OF CHEMORESISTANCE IN GLIOBLASTOMA
Authors: Ahmed Atique 
Published: March 2021

Abstract
Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumor is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is glioblastoma cells’ ability to adapt to complex changes within the tumor microenvironment. To elucidate this adaptation’s molecular mechanisms, specifically during chemotherapy temozolomide, we employed chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ALR13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with Liquid Chromatography-Mass Spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5’-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction function as a negative regulator for purine salvaging. Inhibition of ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using a Food and Drug Administration-approved drug, Mycophenolate Mofetil, that can block the IMPDH2 activity and enhance the therapeutic efficacy of TMZ. Our results suggest and support clinical evaluation of MMF in combination with TMZ treatment in glioma patients.
DDRE-15. THE EVOLUTIONARY ENIGMA OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Oatman Nicole , Dasgupta Biplab 
Published: March 2021

Abstract
Fatty acid desaturation is an enzymatic reaction in which a double bond is introduced into an acyl chain. Of the four functionally distinct desaturase subfamilies, the First Desaturase Family of enzymes introduce the first double bond into a saturated fatty acid, resulting in the synthesis of monounsaturated fatty acids (MUFA). MUFA are essential components of membrane and storage lipids and exert a profound influence on the fluidity of biological membranes. A disequilibrium in saturated to unsaturated fatty acid ratio alters cell growth, differentiation and response to external stimuli, and thus affects a range of pathologies including cancer. The most abundant and key First Desaturase Family enzyme is the delta 9 desaturate called Stearoyl Co-A Desaturase (SCD and SCD5 in humans, and SCD1-4 in mice). SCD desaturates Stearoyl-CoA (C18) and palmitoyl-CoA (C16) to oleoyl-CoA (C18:1) and palmitoyl-CoA (C16:1), respectively. Besides SCD, the only known First Desaturase in mammals with dual function is FADS2 which desaturates palmitate to Sapienate (C16:1, a positional isomer of palmitoleate) in skin cells. A recent study showed that some cancer cells can use FADS2 to bypass the SCD reaction. SCD and SCD5 are by far the most abundant desaturases expressed in the human brain. We made an unexpected discovery that SCD undergoes monoallelic codeletion with PTEN on chromosome 10, and is also highly methylated in glioblastoma (GBM). More surprisingly, all GBM cell lines with SCD codeletion/methylation (that expressed very little SCD protein) are completely resistant to SCD/SCD5 inhibition, yet their phospholipids contained abundant oleic acid. It is unknown if GBMs bypassed SCD, but retained the delta 9 desaturation reaction through a novel enzymatic activity. Our targeted and untargeted metabolomics studies revealed unexpected findings that cannot be explained by conventional wisdom, and may lead to identification of novel lipogenic targets in GBM.
DDRE-22. TARGETING SERINE SYNTHESIS IN BRAIN METASTASIS
Authors: Ngo Bryan , Kim Eugenie , Osorio-Vasquez Victoria , Doll Sophia , Bustraan Sophia , Liang Roger , Luengo Alba , Davidson Shawn , Ali Ahmed , Ferraro Gino , Fischer Grant , Plasger Ariana , Rajasekhar Vinagolu , Kastenhuber Edward , Eskandari Roozbeh , Bacha Sarah , Sriram Roshan , Bakhoum Samuel , Snuderl Matija , Cotzia Paolo , Healey John , Sabatini David , Jones Drew , Zhao Jean , Yu Min , Jain Rakesh , Keshari Kayvan , Davies Michael , Heiden Matthew Vander , Hernando Eva , Mann Matthias , Cantley Lewis , Pacold Michael 
Published: March 2021

Abstract
The brain environment is low in amino acids, including serine and glycine, both of which are important for tumor growth as they are precursors of proteins and nucleotide bases. How tumor cells overcome these conditions to proliferate and survive in the brain is incompletely understood. Here, we show that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first and rate-limiting step of glucose-derived serine synthesis, enables brain metastasis in multiple human types and in preclinical models. Genetic suppression and small molecule inhibition of PHGDH attenuated brain metastasis, but not extra cranial tumors, and improved the overall survival of mice bearing brain metastasis. These results demonstrate that the tumor nutrient microenvironment determines tumor cell sensitivity to loss of serine synthesis pathway activity and raise the possibility that serine synthesis inhibitors may be useful in the treatment of brain metastases.
DDRE-27. IDH MUTATED GLIOMAS PROMOTE EPILEPTOGENESIS VIA D-2-HYDROXYGLUTARATE DEPENDENT MTOR HYPERACTIVATION
Authors: Mortazavi Armin , Fayed Islam , Bachani Muzna , Dowdy Tyrone , Steiner Joseph , Maric Dragan , Yang Chun Zhang , Larion Mioara , Ksendzovsky Alexander , Zaghloul Kareem 
Published: March 2021

Abstract

INTRODUCTION
Epileptic seizures in patients with low-grade, isocitrate dehydrogenase (IDH) mutated gliomas reach 90%, a major source of morbidity for these patients. Albeit there are multiple features that contribute to tumor related epileptogenesis, IDH mutations are determined to be an independent factor, although the pathogenesis remains poorly understood. We demonstrate IDH-mutated tumors promote epileptogenesis through D-2-hydroxyglutarate (D-2-HG) dependent mTOR hyperactivation and metabolic reprogramming.

METHODS
Human epileptic and nonepileptic cortex were identified via subdural electrodes in patients with IDH-mutated gliomas (n=5). An in vitro rat cortical neuronal model on microelectrode arrays were utilized to investigate the role of D-2-HG on neuronal excitability. mTOR and lysine demethylase (KDM) modulators were applied to elucidate the epileptogenic mechanism. Tetrodotoxin was utilized to evaluate the contribution of neuronal activity to mTOR signaling and metabolism. mTOR signaling was evaluated through western blot analysis and multiplex immunofluorescence. Metabolic function were analyzed via Seahorse assays and metabolomic analysis.

RESULTS
D-2-HG increased normalized bursting rate in the neuronal cultures (p&lt;0.0001). Inhibition of mTOR with rapamycin corrected bursting levels to control levels. Furthermore, D-2-HG induced mTOR hyperactivation, independent of bursting activity, which correlated with upregulation of mTOR signaling in human epileptic tissue. KDM inhibition resulted in mTOR hyperactivation and neuronal hyperexcitability, which we demonstrated with D-2-HG, succinate, and PFI-90, a small molecule KDM inhibitor. Epileptic cortex and D-2-HG-treated neurons, have distinct metabolisms independent of neuronal activity compared to peritumoral nonepileptic cortex and control, respectively.

CONCLUSION
We demonstrate IDH-mutated gliomas promote epileptogenesis through a D-2-HG dependent mTOR hyperactivation via KDM inhibition, a putative mechanism and potential therapeutic targets. Furthermore, we argue mTOR hyperactivation results in metabolic reprogramming, independent of neuronal firing, which may contribute to epileptogenesis, a heretofore unrecognized aspect of pathologic mTOR signaling in neurological diseases.
DDRE-28. MECHANISTIC AND THERAPEUTIC LINKS BETWEEN PURINE BIOSYNTHESIS AND DNA DAMAGE IN GLIOBLASTOMA
Authors: Scott Andrew , Zhou Weihua , Wilder-Romans Kari , Feng Jiane , Wu Zhe , Andren Anthony , Zhang Li , Sajjakulnukit Peter , Kachman Maureen , Umemura Yoshie , Schmitt Melanie , Qi Nathan , Lawrence Theodore , Lyssiotis Costas , Wahl Daniel 
Published: March 2021

Abstract
Glioblastoma (GBM) is the most common and aggressive adult brain cancer. Radiation therapy (RT) is a critical treatment modality, and development of RT resistance is the predominant cause of recurrence and mortality in GBM patients. Using cell line models as well as patient-derived xenografts and neurospheres in orthotopic brain tumor models, we have identified increased rates and dependence upon de novo purine biosynthesis as a hallmark of GBM RT resistance. More recently, we have discovered that radiation treatment acutely stimulates flux through de novo purine synthesis in cell line and neurosphere models of GBM. This RT-induced increase in de novo purine synthesis is dependent on signaling through the DNA damage response and thus appears to be an adaptive mechanism to supply purines to repair radiation-induced DNA damage. To determine whether this regulatory mechanism also exists in vivo, we have used advanced metabolomic and metabolic tracing techniques with 13C-labeled glucose and 15N-labeled glutamine in mice bearing RT-resistant GBM patient-derived orthotopic brain tumors. We found that that orthotopic GBM PDXs had elevated activity of de novo purine synthesis that increased further after RT, while normal cortex had little activity even after RT. These observations have therapeutic relevance, as targeting this metabolic pathway with the FDA-approved purine biosynthesis inhibitor mycophenolate mofetil (MMF) overcomes GBM radiation resistance in mouse models in vivo. The lack of de novo purine synthesis in normal cortex suggests that targeting this pathway may be tumor specific. Collectively our data suggest that de novo synthesis of purines mediates RT resistance in GBM and that treatment of brain tumors with MMF in combination with RT may be a promising therapeutic strategy in patients.