bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma
Authors: Xi Xiaonan , Liu Ning , Wang Qianqian , Chu Yahui , Yin Zheng , Ding Yahui , Lu Yaxin 
Published: October 2019

AbstractPAI-1 plays significant roles in cancer occurrence, relapse and multidrug resistance and is highly expressed in tumours. ACT001, which is currently in phase I clinical trials for the treatment of glioblastoma (GBM). However, the detailed molecular mechanism of ACT001 is still unclear. In this study, we investigated the effects of ACT001 on glioma cell proliferation and clarified its mechanism. We discovered that PAI-1 was the direct target of ACT001 by a cellular thermal shift assay. Then, the interaction between ACT001 and PAI-1 was verified by Biacore assays, thermal stability assays and ACT001 probe assays. Furthermore, from the proteomic analysis, we found that ACT001 directly binds PAI-1 to inhibit the PI3K/AKT pathway, which induces the inhibition of glioma cell proliferation, invasion and migration. Moreover, the combination of ACT001 and cisplatin showed a synergistic effect on the inhibition of glioma in vitro and in vivo. In conclusion, our findings demonstrate that PAI-1 is a new target of ACT001, the inhibition of PAI-1 induces glioma inhibition, and ACT001 has a synergistic effect with cisplatin through the inhibition of the PAI-1/PI3K/AKT pathway.
Progranulin attenuates liver fibrosis by downregulating the inflammatory response
Authors: Yoo Wonbeak , Lee Jaemin , Noh Kyung Hee , Lee Sangmin , Jung Dana , Kabir Mohammad Humayun , Park Dongmin , Lee Cheolju , Kwon Ki-Sun , Kim Ji-Su , Kim Seokho 
Published: October 2019

AbstractProgranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine‐choline‐deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-κB) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNF)-α or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease.
c-Myc shuttled by tumour-derived extracellular vesicles promotes lung bronchial cell proliferation through miR-19b and miR-92a
Authors: Borzi Cristina , Calzolari Linda , Ferretti Anna M. , Caleca Laura , Pastorino Ugo , Sozzi Gabriella , Fortunato Orazio 
Published: October 2019

AbstractLung cancer causes approximately one fifth of all cancer deaths. Tumour cells actively communicate with the surrounding microenvironment to support malignant progression. Extracellular vesicles (EVs) play a pivotal role in intercellular communication and modulate recipient cells by delivering their contents, including proteins and nucleic acids such as microRNAs (miRNAs). We isolated EVs from the conditioned medium (CM) of human lung cancer cell lines and plasma of lung cancer patients and cancer-free smokers using an ultracentrifugation method. A significant increase in bronchial HBEC-KRASV12high cell proliferation, confirmed by cell cycle analysis, was observed after treatment with cancer-derived EVs. Lung cancer-derived EVs induced transcription of the pri-miR-92a gene, resulting in the overexpression of mature miR-19b and miR-92a in recipient bronchial cells. Modulation of these two miRNAs using miRNA mimics or inhibitors confirmed their ability to promote proliferation. In silico analysis and experimental validation showed that miR-19b and miR-92a impaired the TGF-beta (TGFB) pathway and identified TGFBRI and TGFBRII as target genes involved in EV-mediated bronchial cell proliferation. Interestingly, the oncoprotein c-Myc, a well-known miR-17-92 cluster activator, was detected only in the EVs derived from lung cancer patients and cell lines and was able to modulate the proliferation of HBEC-KRASV12high recipient cells. These data support the role of c-Myc shuttling in lung cancer-derived EVs in inducing the upregulation of onco-miR-19b and miR-92a expression with concomitant impairment of the TGFB signalling pathway in recipient cells.
Genome editing for horticultural crop improvement
Authors: Xu Jiemeng , Hua Kai , Lang Zhaobo 
Published: October 2019

AbstractHorticultural crops provide humans with many valuable products. The improvement of the yield and quality of horticultural crops has been receiving increasing research attention. Given the development and advantages of genome-editing technologies, research that uses genome editing to improve horticultural crops has substantially increased in recent years. Here, we briefly review the different genome-editing systems used in horticultural research with a focus on clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated genome editing. We also summarize recent progress in the application of genome editing for horticultural crop improvement. The combination of rapidly advancing genome-editing technology with breeding will greatly increase horticultural crop production and quality.
Democratized image analytics by visual programming through integration of deep models and small-scale machine learning
Authors: Godec Primož , Pančur Matjaž , Ilenič Nejc , Čopar Andrej , Stražar Martin , Erjavec Aleš , Pretnar Ajda , Demšar Janez , Starič Anže , Toplak Marko , Žagar Lan , Hartman Jan , Wang Hamilton , Bellazzi Riccardo , Petrovič Uroš , Garagna Silvia , Zuccotti Maurizio , Park Dongsu , Shaulsky Gad , Zupan Blaž 
Published: October 2019

AbstractAnalysis of biomedical images requires computational expertize that are uncommon among biomedical scientists. Deep learning approaches for image analysis provide an opportunity to develop user-friendly tools for exploratory data analysis. Here, we use the visual programming toolbox Orange (http://orange.biolab.si) to simplify image analysis by integrating deep-learning embedding, machine learning procedures, and data visualization. Orange supports the construction of data analysis workflows by assembling components for data preprocessing, visualization, and modeling. We equipped Orange with components that use pre-trained deep convolutional networks to profile images with vectors of features. These vectors are used in image clustering and classification in a framework that enables mining of image sets for both novel and experienced users. We demonstrate the utility of the tool in image analysis of progenitor cells in mouse bone healing, identification of developmental competence in mouse oocytes, subcellular protein localization in yeast, and developmental morphology of social amoebae.
Rapid selection and identification of functional CD8+ T cell epitopes from large peptide-coding libraries
Authors: Sharma Govinda , Rive Craig M. , Holt Robert A. 
Published: October 2019

AbstractCytotoxic CD8+ T cells recognize and eliminate infected or malignant cells that present peptide epitopes derived from intracellularly processed antigens on their surface. However, comprehensive profiling of specific major histocompatibility complex (MHC)-bound peptide epitopes that are naturally processed and capable of eliciting a functional T cell response has been challenging. Here, we report a method for deep and unbiased T cell epitope profiling, using in vitro co-culture of CD8+ T cells together with target cells transduced with high-complexity, epitope-encoding minigene libraries. Target cells that are subject to cytotoxic attack from T cells in co-culture are isolated prior to apoptosis by fluorescence-activated cell sorting, and characterized by sequencing the encoded minigenes. We then validate this highly parallelized method using known murine T cell receptor/peptide-MHC pairs and diverse minigene-encoded epitope libraries. Our data thus suggest that this epitope profiling method allows unambiguous and sensitive identification of naturally processed and MHC-presented peptide epitopes.
Galactose to tagatose isomerization at moderate temperatures with high conversion and productivity
Authors: Bober Josef R. , Nair Nikhil U. 
Published: October 2019

AbstractThere are many industrially-relevant enzymes that while active, are severely limited by thermodynamic, kinetic, or stability issues (isomerases, lyases, transglycosidases). In this work, we study Lactobacillus sakeil-arabinose isomerase (LsLAI) for d-galactose to d-tagatose isomerization—that is limited by all three reaction parameters. The enzyme demonstrates low catalytic efficiency, low thermostability at temperatures > 40 °C, and equilibrium conversion < 50%. After exploring several strategies to overcome these limitations, we show that encapsulating LsLAI in gram-positive Lactobacillus plantarum that is chemically permeabilized enables reactions at high rates, high conversions, and elevated temperatures. In a batch process, this system enables ~ 50% conversion in 4 h starting with 300 mM galactose (an average productivity of 37 mM h−1), and 85% conversion in 48 h. We suggest that such an approach may be invaluable for other enzymatic processes that are similarly kinetically-, thermodynamically-, and/or stability-limited.
Detecting relapse in youth with psychotic disorders utilizing patient-generated and patient-contributed digital data from Facebook
Authors: Birnbaum M. L. , Ernala S. K. , Rizvi A. F. , Arenare E. , R. Van Meter A. , De Choudhury M. , Kane J. M. 
Published: October 2019

AbstractAlthough most patients who experience a first-episode of psychosis achieve remission of positive psychotic symptoms, relapse is common. Existing relapse evaluation strategies are limited by their reliance on direct and timely contact with professionals, and accurate reporting of symptoms. A method by which to objectively identify early relapse warning signs could facilitate swift intervention. We collected 52,815 Facebook posts across 51 participants with recent onset psychosis (mean age = 23.96 years; 70.58% male) and applied anomaly detection to explore linguistic and behavioral changes associated with psychotic relapse. We built a one-class classification model that makes patient-specific personalized predictions on risk to relapse. Significant differences were identified in the words posted to Facebook in the month preceding a relapse hospitalization compared to periods of relative health, including increased usage of words belonging to the swear (p < 0.0001, Wilcoxon signed rank test), anger (p < 0.001), and death (p < 0.0001) categories, decreased usage of words belonging to work (p = 0.00579), friends (p < 0.0001), and health (p < 0.0001) categories, as well as a significantly increased use of first (p < 0.0001) and second-person (p  < 0.001) pronouns. We additionally observed a significant increase in co-tagging (p < 0.001) and friending (p < 0.0001) behaviors in the month before a relapse hospitalization. Our classifier achieved a specificity of 0.71 in predicting relapse. Results indicate that social media activity captures objective linguistic and behavioral markers of psychotic relapse in young individuals with recent onset psychosis. Machine-learning models were capable of making personalized predictions of imminent relapse hospitalizations at the patient-specific level.
Blue Carbon stock in Zostera noltei meadows at Ria de Aveiro coastal lagoon (Portugal) over a decade
Authors: Sousa Ana I. , da Silva José Figueiredo , Azevedo Ana , Lillebø Ana I. 
Published: October 2019

AbstractThis work assessed the Blue Carbon (C) stock in the seagrass meadows (Zostera noltei) of Ria de Aveiro coastal lagoon (Portugal), and evaluated its spatio-temporal trend over the 2003–2005 to 2013–2014 period. Zostera noltei spatial distribution, restricted to intertidal areas in 2014, was mapped by remote sensing using an unmanned aerial vehicle (UAV) and aerial photography. Zostera noltei biomass was also monitored in situ over a year and its Blue C stock was estimated. By 2014, intertidal meadows covered an area of 226 ± 4 ha and their Blue C stock ranged from 227 ± 6 to 453 ± 13 Mg C. Overall, Ria de Aveiro Z. noltei intertidal meadows increased in extent over the 2003–2005 to 2013–2014 period, corroborating the recent declining trend reversal observed in Europe and contrary to the global decline trend. This spatio-temporal shift might be related to a natural adjustment of the intertidal meadows to past human intervention in Ria de Aveiro, namely large-scale dredging activities, particularly in the 1996–1998 period, combined with the more accurate assessment performed in 2014 using the UAV. This recovery contributes to the effective increase of the Blue C stock in Ria de Aveiro and, ultimately, to supporting climate regulation and improving ecosystem health. However, major dredging activities are foreseen in the system’s management plan, which can again endanger the recovery trend of Z. noltei intertidal meadows in Ria de Aveiro.
Estimation of nephron number in living humans by combining unenhanced computed tomography with biopsy-based stereology
Authors: Sasaki Takaya , Tsuboi Nobuo , Okabayashi Yusuke , Haruhara Kotaro , Kanzaki Go , Koike Kentaro , Kobayashi Akimitsu , Yamamoto Izumi , Takahashi Sho , Ninomiya Toshiharu , Shimizu Akira , Rule Andrew D. , Bertram John F. , Yokoo Takashi 
Published: October 2019

AbstractMethods for estimating nephron number in a clinical setting may be useful for predicting renal outcomes. This study aimed to establish such a method using unenhanced computed tomography (CT) and biopsy-based stereology. Patients or living kidney donors simultaneously subjected to enhanced and unenhanced CT examinations were randomly assigned to development and validation groups. The enhanced CT-measured arterial phase and the venous phase images of kidneys were regarded as the true values for cortical volume and parenchymal volume, respectively. Linear multiple regression analysis was used to create models for estimating cortical volume using explanatory variables including unenhanced CT-measured parenchymal volume. Nephron number was determined as the product of cortical volume and the glomerular density in biopsies of donors. Five equations for estimating cortical volume were created and verified. In donors, estimated nephron number by unenhanced CT was consistent with that by enhanced CT, with minimal errors in all models (636–655 ± 210–219 vs. 648 ± 224 × 103/kidney). Clinical characteristics combined with parenchymal volume did not improve the equation over parenchymal volume alone. These results support the feasibility of estimating nephron number by a combination of unenhanced CT and biopsy-based stereology, with a possible application for renal disease patients who are often not suitable for contrast media.
Biphasic adverse effect of titanium nanoparticles on testicular function in mice
Authors: Miura Nobuhiko , Ohtani Katsumi , Hasegawa Tatsuya , Yoshioka Hiroki , Hwang Gi-Wook 
Published: October 2019

AbstractThe male reproductive system is being recognized as toxic targets of nanoparticles including titanium dioxide nanoparticles (TiNP). Most of these reports are, however, obtained from the results of long-term exposure of TiNP. In this study, we diversely examined the acute effects of TiNP on the male reproductive system. Male C57BL/6J mice were administered a single intravenous injection of TiNP (10, 50 mg/kg), and were sacrificed at 1, 3, and 9 days post-injection. Testicular functions (estimated by sperm motility and sperm number) were measured via computer-assisted sperm analysis (CASA). Results indicated that sperm motility was significantly reduced from 1 day following TiNP injection (in both dose), and this reduction persisted up to 9 days post-TiNP injection (10 mg/kg injection group). Interestingly, we observed no significant decrease in sperm numbers in both the testis and the cauda epididymis in either treatment groups during the course of the experiment. Therefore, we hypothesized that TiNP may target the mature spermatozoa. In addition, sperm suspensions directly incubated with TiNP showed reduced sperm motility, [3H]-thymidine incorporation, and ATP level. Our results indicated that TiNP possesses “biphasic effects”; the obstacles to mature sperms (short term effect) in addition to the impairment in testis (long-term effect).
Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis
Authors: Quan Diana H. , Nagalingam Gayathri , Luck Ian , Proschogo Nicholas , Pillalamarri Vijaykumar , Addlagatta Anthony , Martinez Elena , Sintchenko Vitali , Rutledge Peter J. , Triccas James A. 
Published: October 2019

AbstractMycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.
Educational inequality in physician-diagnosed hypertension widened and persisted among women from 1999 to 2014 in Hong Kong
Authors: Chung Gary K. K. , Lai Francisco T. T. , Yeoh Eng-Kiong , Chung Roger Y. 
Published: October 2019

AbstractGender differences in the trend of educational inequality in hypertension have been observed especially in the Asian populations, indicating the increasing importance of education as a social determinant of hypertension among women. This study examined the gender-specific trends of educational inequality in physician-diagnosed hypertension in Hong Kong between 1999 and 2014. Based on a series of eight government-led territory-wide household surveys conducted between 1999 and 2014, 97,481 community-dwelling Hong Kong Chinese adults aged 45 or above were analysed. The extent and trend of gender-specific educational inequality in self-reported physician-diagnosed hypertension were estimated by regression-based Relative Index of Inequality and age-standardised Slope Index of Inequality. Over the study period, age-standardised prevalence of self-reported hypertension increased in both genders, with the greatest prevalence among the least educated women. Educational inequalities in hypertension significantly widened in female from 1999 to 2009 and persisted thereafter; nonetheless, the respective inequality was negligible in male. Further adjustment for household income did not attenuate the observed inequality. To conclude, a widened and then persistent discrepancy in hypertension across education levels was observed among women, but not among men, in Hong Kong. The gender perspective should be carefully considered when designing hypertension prevention strategies and related health policies.
A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo
Authors: Santos Leonardo , Colman Laura , Contreras Paola , Chini Claudia C. , Carlomagno Adriana , Leyva Alejandro , Bresque Mariana , Marmisolle Inés , Quijano Celia , Durán Rosario , Irigoín Florencia , Prieto-Echagüe Victoria , Vendelbo Mikkel H. , Sotelo-Silveira José R. , Chini Eduardo N. , Badano Jose L. , Calliari Aldo J. , Escande Carlos 
Published: October 2019

AbstractThe protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.