bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1
Authors: Igarashi Ryoko , Yamashita Shun-ichi , Yamashita Tomohiro , Inoue Keiichi , Fukuda Tomoyuki , Fukuchi Takeo , Kanki Tomotake 
Published: January 2020

AbstractMitophagy plays an important role in the maintenance of mitochondrial homeostasis. PTEN-induced kinase (PINK1), a key regulator of mitophagy, is degraded constitutively under steady-state conditions. During mitophagy, it becomes stabilized in the outer mitochondrial membrane, particularly under mitochondrial stress conditions, such as in treatment with uncouplers, generation of excessive mitochondrial reactive oxygen species, and formation of protein aggregates in mitochondria. Stabilized PINK1 recruits and activates E3 ligases, such as Parkin and mitochondrial ubiquitin ligase (MUL1), to ubiquitinate mitochondrial proteins and induce ubiquitin-mediated mitophagy. Here, we found that the anticancer drug gemcitabine induces the stabilization of PINK1 and subsequent mitophagy, even in the absence of Parkin. We also found that gemcitabine-induced stabilization of PINK1 was not accompanied by mitochondrial depolarization. Interestingly, the stabilization of PINK1 was mediated by MUL1. These results suggest that gemcitabine induces mitophagy through MUL1-mediated stabilization of PINK1 on the mitochondrial membrane independently of mitochondrial depolarization.
Molecular level study of hot water extracted green tea buried in soils - a proxy for labile soil organic matter
Authors: Bell Nicholle G. A. , Smith Alan J. , Zhu Yufan , Beishuizen William H. , Chen Kangwei , Forster Dan , Ji Yiran , Knox Elizabeth A. 
Published: January 2020

AbstractUnderstanding the composition of soil organic matter (SOM) is vital to our understanding of how soils form, evolve and respond to external stimuli. The shear complexity of SOM, an inseparable mixture of thousands of compounds hinders the determination of structure-function relationships required to explore these processes on a molecular level. Litter bags and soil hot water extracts (HWE) have frequently been used to study the transformation of labile SOM, however these are still too complex to examine beyond compound classes. In this work, a much simpler mixture, HWE buried green tea, was investigated by Nuclear Magnetic Resonance (NMR) spectroscopy and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS), as a proxy for labile SOM. Changes induced by the burial over 90 days in a grassland, woodland and two peatland sites, one damaged by drainage and one undergoing restoration by drain-blocking, were analysed. Major differences between the extracts were observed on the level of compound classes, molecular formulae and specific molecules. The causes of these differences are discussed with reference to abiotic and biotic processes. Despite the vastly different detection limits of NMR and MS, chemometric analysis of the data yielded identical separation of the samples. These findings provide a basis for the molecular level interrogation of labile SOM and C-cycling processes in soils.
miRgo: integrating various off-the-shelf tools for identification of microRNA–target interactions by heterogeneous features and a novel evaluation indicator
Authors: Chu Yen-Wei , Chang Kai-Po , Chen Chi-Wei , Liang Yu-Tai , Soh Zhi Thong , Hsieh Li‐Ching 
Published: January 2020

AbstractMicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression and biological processes through binding to messenger RNAs. Predicting the relationship between miRNAs and their targets is crucial for research and clinical applications. Many tools have been developed to predict miRNA–target interactions, but variable results among the different prediction tools have caused confusion for users. To solve this problem, we developed miRgo, an application that integrates many of these tools. To train the prediction model, extreme values and median values from four different data combinations, which were obtained via an energy distribution function, were used to find the most representative dataset. Support vector machines were used to integrate 11 prediction tools, and numerous feature types used in these tools were classified into six categories—binding energy, scoring function, evolution evidence, binding type, sequence property, and structure—to simplify feature selection. In addition, a novel evaluation indicator, the Chu-Hsieh-Liang (CHL) index, was developed to improve the prediction power in positive data for feature selection. miRgo achieved better results than all other prediction tools in evaluation by an independent testing set and by its subset of functionally important genes. The tool is available at http://predictor.nchu.edu.tw/miRgo.
Methylenetetrahydrofolate reductase C677T polymorphism is not associated with the risk of nonsyndromic cleft lip/palate: An updated meta-analysis
Authors: Imani Mohammad Moslem , Golchin Negin , Safaei Mohsen , Rezaei Farzad , Abbasi Hooshyar , Sadeghi Masoud , Lopez-Jornet Pia , Mozaffari Hamid Reza , Sharifi Roohollah 
Published: January 2020

AbstractBoth genetic and environmental factors affect the risk of orofacial clefts. The present meta-analysis aimed to evaluate the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and risk of nonsyndromic cleft lip/palate (NSCL/P) in cases-control studies. The PubMed/Medline, Scopus, Web of Science, and Cochrane Library databases were searched up to April 2019 with no restrictions. The odds ratios (ORs) and 95% confidence intervals (CIs) in all analyses were calculated by Review Manager 5.3 software. The funnel plot analysis was carried out by the Comprehensive Meta-Analysis version 2.0 software. Subgroup analysis, meta-regression, and sensitivity analysis were performed for the pooled analyses. Thirty-one studies reviewed in this meta-analysis included 4710 NSCL/P patients and 7271 controls. There was no significant association between MTHFR C677T polymorphism and NSCL/P susceptibility related to allelic model (OR = 1.04; P = 0.49), homozygote model (OR = 1.11; P = 0.35), heterozygote model (OR = 0.99; P = 0.91), dominant model (OR = 1.00; P = 0.96), or recessive model (OR = 1.08; P = 0.23). There was no significant association between MTHFR C677T polymorphism and NSCL/P susceptibility based on the ethnicity or the source of cases. There was a significant linear relationship between the year of publication and log ORs for the allele model. The results of the present meta-analysis failed to show an association between MTHFR C677T polymorphism and NSCL/P susceptibility. The subgroup analyses based on the ethnicity and the source of cases further confirmed this result.
Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions
Authors: Thézénas Marie-Laëtitia , De Leo Bianca , Laux-Biehlmann Alexis , Bafligil Cemsel , Elger Bernd , Tapmeier Thomas , Morten Karl , Rahmioglu Nilufer , Dakin Stephanie G. , Charles Philip , Martinez Fernando Estrada , Steers Graham , Fischer Oliver M. , Mueller Joerg , Hess-Stumpp Holger , Steinmeyer Andreas , Manek Sanjiv , Zondervan Krina T. , Kennedy Stephen , Becker Christian M. , Shang Catherine , Zollner Thomas M. , Kessler Benedikt M. , Oppermann Udo 
Published: January 2020

AbstractEndometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.
Supramolecular tholos-like architecture constituted by archaeal proteins without functional annotation
Authors: Yagi-Utsumi Maho , Sikdar Arunima , Song Chihong , Park Jimin , Inoue Rintaro , Watanabe Hiroki , Burton-Smith Raymond N. , Kozai Toshiya , Suzuki Tatsuya , Kodama Atsuji , Ishii Kentaro , Yagi Hirokazu , Satoh Tadashi , Uchiyama Susumu , Uchihashi Takayuki , Joo Keehyoung , Lee Jooyoung , Sugiyama Masaaki , Murata Kazuyoshi , Kato Koichi 
Published: January 2020

AbstractEuryarchaeal genomes encode proteasome-assembling chaperone homologs, PbaA and PbaB, although archaeal proteasome formation is a chaperone-independent process. Homotetrameric PbaB functions as a proteasome activator, while PbaA forms a homopentamer that does not interact with the proteasome. Notably, PbaA forms a complex with PF0014, an archaeal protein without functional annotation. In this study, based on our previous research on PbaA crystal structure, we performed an integrative analysis of the supramolecular structure of the PbaA/PF0014 complex using native mass spectrometry, solution scattering, high-speed atomic force microscopy, and electron microscopy. The results indicated that this highly thermostable complex constitutes ten PbaA and ten PF0014 molecules, which are assembled into a dumbbell-shaped structure. Two PbaA homopentameric rings correspond to the dumbbell plates, with their N-termini located outside of the plates and C-terminal segments left mobile. Furthermore, mutant PbaA lacking the mobile C-terminal segment retained the ability to form a complex with PF0014, allowing 3D modeling of the complex. The complex shows a five-column tholos-like architecture, in which each column comprises homodimeric PF0014, harboring a central cavity, which can potentially accommodate biomacromolecules including proteins. Our findings provide insight into the functional roles of Pba family proteins, offering a novel framework for designing functional protein cages.
5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice
Authors: Hamzaoui Mouad , Djerada Zoubir , Brunel Valery , Mulder Paul , Richard Vincent , Bellien Jérémy , Guerrot Dominique 
Published: January 2020

AbstractExperimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice.
Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury
Authors: Nomura-Komoike Kaori , Saitoh Fuminori , Fujieda Hiroki 
Published: January 2020

AbstractMüller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N–nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.
Heat transfer enhancement using CO2 in a natural circulation loop
Authors: Thippeswamy L. R. , Kumar Yadav Ajay 
Published: January 2020

AbstractThe natural circulation loop (NCL) is a highly reliable and noise-free heat transfer device due to the absence of moving components. Working fluid used in the natural circulation loop plays an important role in enhancing the heat transfer capability of the loop. This experimental study investigates the subcritical and supercritical heat transfer performance of a natural circulation loop (NCL) with CO2 as the working fluid. Operating pressures and temperatures are varied in such a way that the loop fluid should remain in the specified state (subcooled liquid, two-phase, superheated vapor, supercritical). Water and methanol are used as external fluids in cold and hot heat exchangers for temperatures above zero and below zero (in °C) respectively, depending on operating temperature. For loop fluids, the performance of CO2 is compared with water for above zero and with brine solution for the subzero case. Further, the impact of loop operating pressure (35–90 bar) on the performance of the system is also studied. For hot heat exchanger inlet temperature (5 to 70 °C) and cold heat exchanger inlet temperature (−18 to 32 °C), it was observed that the maximum heat transfer rates in the case of subcritical vapor, subcritical liquid, two-phase and supercritical CO2 based systems are 400%, 500%, 900%, and 800% higher than the water/brine-based system respectively.
Identification of synergistic drug combinations using breast cancer patient-derived xenografts
Authors: Turner Tia H. , Alzubi Mohammad A. , Harrell J. Chuck 
Published: January 2020

AbstractCompared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basal-like PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC.
Co-existence of PrPD types 1 and 2 in sporadic Creutzfeldt-Jakob disease of the VV subgroup: phenotypic and prion protein characteristics
Authors: Cali Ignazio , Puoti Gianfranco , Smucny Jason , Curtiss Paul Michael , Cracco Laura , Kitamoto Tetsuyuki , Occhipinti Rossana , Cohen Mark Lloyd , Appleby Brian Stephen , Gambetti Pierluigi 
Published: January 2020

AbstractWe report a detailed study of a cohort of sporadic Creutzfeldt-Jakob disease (sCJD) VV1–2 type-mixed cases (valine homozygosity at codon 129 of the prion protein, PrP, gene harboring disease-related PrP, PrPD, types 1 and 2). Overall, sCJDVV1–2 subjects showed mixed clinical and histopathological features, which often correlated with the relative amounts of the corresponding PrPD type. However, type-specific phenotypic characteristics were only detected when the amount of the corresponding PrPD type exceeded 20–25%. Overall, original features of types 1 (T1) and 2 (T2) in sCJDVV1 and -VV2, including rostrocaudal relative distribution and conformational indicators, were maintained in sCJDVV1–2 except for one of the two components of T1 identified by electrophoretic mobility as T121. The T121 conformational characteristics shifted in the presence of T2, inferring a conformational effect of PrPD T2 on T121. The prevalence of sCJDVV1–2 was 23% or 57% of all sCJDVV cases, depending on whether standard or highly sensitive type-detecting procedures were adopted. This study, together with previous data from sCJDMM1–2 (methionine homozygosity at PrP gene codon 129) establishes the type-mixed sCJD variants as an important component of sCJD, which cannot be identified with current non-tissue based diagnostic tests of prion disease.
KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion
Authors: Oladimeji Peter O. , Bakke Jesse , Wright William C. , Chen Taosheng 
Published: January 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. One major reason for this is that PDAC quickly metastasizes to other organs, thereby making its treatment difficult. The molecular machinery driving PDAC metastasis is still poorly understood. In this study, we applied an unbiased approach using CRISPR screening to identify genes that strongly regulate invasion (based on an in vitro assessment of their metastatic potential) in PANC-1, a PDAC cell line. Through CRISPR screening, we identified MBNL3 and KANSL2 as strong regulators of invasion in PANC-1 cells. We further validated MBNL3 and KANSL2 as regulators of PANC-1 cell invasion by using the doxycycline-inducible shRNA system. We also showed that MBNL3 and KANSL2 do not affect cell proliferation. Through our efforts, we have established a process to identify genes that regulate cell invasion and can be further investigated as potential targets for therapeutic intervention.
Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus
Authors: Hitakarun Atitaya , Khongwichit Sarawut , Wikan Nitwara , Roytrakul Sittiruk , Yoksan Sutee , Rajakam Supoth , Davidson Andrew D. , Smith Duncan R. 
Published: January 2020

AbstractMany mosquito transmitted viruses of the genera Alphavirus and Flavivirus are human pathogens of significant concern, and there is currently no specific antiviral for any member of these two genera. This study sought to investigate the broad utility of orlistat (tetrahydrolipstatin) in reducing virus infection for several mosquito borne viruses including flaviviruses (dengue virus (DENV; nine isolates analyzed), Japanese encephalitis virus (JEV; one isolate analyzed) and Zika virus (ZIKV; 2 isolates analyzed)) as well as an alphavirus (chikungunya virus; CHIKV; 2 isolates analyzed). Three different treatment regimens were evaluated, namely pre-treatment (only), post-treatment (only) and pre- and post-treatment, and three factors were evaluated, namely level of infection, virus titer and genome copy number. Results showed that all three treatment modalities were able to significantly reduce virus titer for all viruses investigated, with the exception of three isolates of DENV in the pre-treatment only regimen. Pre- and post-treatment was more effective in reducing the level of infection and genome copy number of all viruses investigated than either pre-treatment or post-treatment alone. Collectively, these results suggest orlistat has potential as a broad-spectrum agent against multiple mosquito transmitted viruses.
Whole-body vibration modulates leg muscle reflex and blood perfusion among people with chronic stroke: a randomized controlled crossover trial
Authors: Huang Meizhen , Miller Tiev , Ying Michael , Pang Marco Y. C. 
Published: January 2020

AbstractThis study aimed to investigate the acute effect of whole-body vibration (WBV) on the reflex and non-reflex components of spastic hypertonia and intramuscular blood perfusion among individuals with chronic stroke. Thirty-six people with chronic stroke (age: 61.4 ± 6.9 years) participated in this randomized controlled cross-over study. Each participant underwent two testing conditions: static standing for 5 minutes with WBV (30 Hz, 1.5 mm) or no-vibration. We assessed the soleus H-reflex, shear modulus (ultrasound elastography) and vascular index (color power Doppler ultrasound) of the medial gastrocnemius (MG) muscle on either paretic or non-paretic side at baseline and every 1-min post-intervention up to 5 minutes. The results revealed a significant inhibition of the H/M ratio bilaterally for the WBV condition (absolute change on paretic side: 0.61 ± 0.35, p = 0.001; non-paretic side: 0.34 ± 0.23, p = 0.001), but not the control condition. The inhibition of H-reflex was sustained up to 4 minutes and 3 minutes on the paretic and non-paretic side, respectively. The vascular index of MG muscle was significantly increased only for the WBV condition [paretic: from 0.55 ± 0.07 to 1.08 ± 0.18 (p = 0.001); non-paretic: from 0.82 ± 0.09 to 1.01 ± 0.13 (p < 0.001)], which lasted for 3 minutes and 5 minutes, respectively. No significant change of the shear modulus in the MG muscle was observed, regardless of the testing condition. Based on our results, WBV had an acute effect on modulating spastic hypertonia dominated by hyperreflexia in people with chronic stroke and facilitating greater intramuscular blood perfusion. No acute effect on passive muscle stiffness was observed.