Personalized Computational Modeling of Left Atrial Geometry and Transmural Myofiber Architecture

Publication date: Available online 5 April 2018
Source:Medical Image Analysis
Author(s): Thomas E Fastl, Catalina Tobon-Gomez, Andrew Crozier, John Whitaker, Ronak Rajani, Karen P McCarthy, Damian Sanchez-Quintana, Siew Y Ho, Mark D O'Neill, Gernot Plank, Martin J Bishop, Steven A Niederer
Atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by complete absence of coordinated atrial contraction and associated with an increased morbidity and mortality. Personalized computational modeling provides a novel framework for integrating and interpreting the role of atrial electrophysiology (EP) including the underlying anatomy and microstructure in the development and sustenance of AF. Coronary computed tomography angiography data were segmented using a statistics-based approach and the smoothed voxel representations were discretized into high-resolution tetrahedral finite element (FE) meshes. To estimate the complex left atrial myofiber architecture, individual fiber fields were generated according to morphological data on the endo- and epicardial surfaces based on local solutions of Laplace's equation and transmurally interpolated to tetrahedral elements. The influence of variable transmural microstructures was quantified through EP simulations on 3 patients using 5 different fiber interpolation functions. Personalized geometrical models included the heterogeneous thickness distribution of the left atrial myocardium and subsequent discretization led to high-fidelity tetrahedral FE meshes. The novel algorithm for automated incorporation of the left atrial fiber architecture provided a realistic estimate of the atrial microstructure and was able to qualitatively capture all important fiber bundles. Consistent maximum local activation times were predicted in EP simulations using individual transmural fiber interpolation functions for each patient suggesting a negligible effect of the transmural myofiber architecture on EP. The established modeling pipeline provides a robust framework for the rapid development of personalized model cohorts accounting for detailed anatomy and microstructure and facilitates simulations of atrial EP.

Graphical abstract

https://ift.tt/2H3V9LE

Statistical testing and power analysis for brain-wide association study

Publication date: Available online 5 April 2018
Source:Medical Image Analysis
Author(s): Weikang Gong, Lin Wan, Wenlian Lu, Liang Ma, Fan Cheng, Wei Cheng, Stefan Grünewald, Jianfeng Feng
The identification of connexel-wise associations, which involves examining functional connectivities between pairwise voxels across the whole brain, is both statistically and computationally challenging. Although such a connexel-wise methodology has recently been adopted by brain-wide association studies (BWAS) to identify connectivity changes in several mental disorders, such as schizophrenia, autism and depression, the multiple correction and power analysis methods designed specifically for connexel-wise analysis are still lacking. Therefore, we herein report the development of a rigorous statistical framework for connexel-wise significance testing based on the Gaussian random field theory. It includes controlling the family-wise error rate (FWER) of multiple hypothesis testings using topological inference methods, and calculating power and sample size for a connexel-wise study. Our theoretical framework can control the false-positive rate accurately, as validated empirically using two resting-state fMRI datasets. Compared with Bonferroni correction and false discovery rate (FDR), it can reduce false-positive rate and increase statistical power by appropriately utilizing the spatial information of fMRI data. Importantly, our method bypasses the need of non-parametric permutation to correct for multiple comparison, thus, it can efficiently tackle large datasets with high resolution fMRI images. The utility of our method is shown in a case-control study. Our approach can identify altered functional connectivities in a major depression disorder dataset, whereas existing methods fail. A software package is available at https://ift.tt/2H20cfC.

Graphical abstract

https://ift.tt/2IzdflN

Genomic and Functional Approaches to Understanding Cancer Aneuploidy

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Alison M. Taylor, Juliann Shih, Gavin Ha, Galen F. Gao, Xiaoyang Zhang, Ashton C. Berger, Steven E. Schumacher, Chen Wang, Hai Hu, Jianfang Liu, Alexander J. Lazar, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

Graphical abstract

Teaser

Analyzing >10,000 human cancers, Taylor et al. show that aneuploidy is correlated with somatic mutation rate, expression of proliferation genes, and decreased leukocyte infiltration. Loss of chromosome arm 3p is common in squamous cancers, but deletion of chromosome 3p reduces cell proliferation in vitro.


https://ift.tt/2qb7V1i

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Yang Liu, Nilay S. Sethi, Toshinori Hinoue, Barbara G. Schneider, Andrew D. Cherniack, Francisco Sanchez-Vega, Jose A. Seoane, Farshad Farshidfar, Reanne Bowlby, Mirazul Islam, Jaegil Kim, Walid Chatila, Rehan Akbani, Rupa S. Kanchi, Charles S. Rabkin, Joseph E. Willis, Kenneth K. Wang, Shannon J. McCall, Lopa Mishra, Akinyemi I. Ojesina, Susan Bullman, Chandra Sekhar Pedamallu, Alexander J. Lazar, Ryo Sakai, Vésteinn Thorsson, Adam J. Bass, Peter W. Laird
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

Graphical abstract

Teaser

Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1.


https://ift.tt/2IvA1uY

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Ashton C. Berger, Anil Korkut, Rupa S. Kanchi, Apurva M. Hegde, Walter Lenoir, Wenbin Liu, Yuexin Liu, Huihui Fan, Hui Shen, Visweswaran Ravikumar, Arvind Rao, Andre Schultz, Xubin Li, Pavel Sumazin, Cecilia Williams, Pieter Mestdagh, Preethi H. Gunaratne, Christina Yau, Reanne Bowlby, A. Gordon Robertson, Daniel G. Tiezzi, Chen Wang, Andrew D. Cherniack, Andrew K. Godwin, Nicole M. Kuderer, Janet S. Rader, Rosemary E. Zuna, Anil K. Sood, Alexander J. Lazar, Akinyemi I. Ojesina, Clement Adebamowo, Sally N. Adebamowo, Keith A. Baggerly, Ting-Wen Chen, Hua-Sheng Chiu, Steve Lefever, Liang Liu, Karen MacKenzie, Sandra Orsulic, Jason Roszik, Carl Simon Shelley, Qianqian Song, Christopher P. Vellano, Nicolas Wentzensen, John N. Weinstein, Gordon B. Mills, Douglas A. Levine, Rehan Akbani
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

Teaser

By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes.


https://ift.tt/2JnGEk9

Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Ying-Nai Wang, Heng-Huan Lee, Chao-Kai Chou, Wen-Hao Yang, Yongkun Wei, Chun-Te Chen, Jun Yao, Jennifer L. Hsu, Cihui Zhu, Haoqiang Ying, Yuanqing Ye, Wei-Jan Wang, Seung-Oe Lim, Weiya Xia, How-Wen Ko, Xiuping Liu, Chang-Gong Liu, Xifeng Wu, Huamin Wang, Donghui Li, Laura R. Prakash, Matthew H. Katz, Yaan Kang, Michael Kim, Jason B. Fleming, David Fogelman, Milind Javle, Anirban Maitra, Mien-Chie Hung
Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families.

Graphical abstract

Teaser

Wang et al. identify angiogenin (ANG) as a ligand for epidermal growth factor receptor (EGFR). ANG-mediated EGFR activation can trigger oncogenic transformation, and high ANG in the plasma of pancreatic adenocarcinoma patients positively correlates with response to the EGFR inhibitor erlotinib.


https://ift.tt/2uT195c

GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Leanne Li, Qiqun Zeng, Arjun Bhutkar, José A. Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M. Luisa Iruela-Arispe, Douglas Hanahan
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

Graphical abstract

Teaser

Li et al. show that GKAP, a scaffold protein of NMDAR, and its downstream effectors FMRP and HSF1 play important roles in the invasive growth of pancreatic tumors. In several cancer types, low NMDAR activity, based on a transcriptomic signature, associates with favorable patient prognosis.


https://ift.tt/2q5L7QM

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Zehua Wang, Bo Yang, Min Zhang, Weiwei Guo, Zhiyuan Wu, Yue Wang, Lin Jia, Song Li, Wen Xie, Da Yang
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Graphical abstract

Teaser

Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes.


https://ift.tt/2uMDzXP

Comparison of Two Protocols of Misoprostol (PGE1) and the Rate of Cesarean Section Due to Failed Induction.

Condition:   Induction of Labor
Interventions:   Procedure: 6 misoprostol;   Procedure: 3 misoprostol
Sponsors:   Saint Thomas Hospital, Panama;   Sistema Nacional de Investigadores de Panamá
Not yet recruiting

https://ift.tt/2JoUqmM

Remote Activity Monitored by Fitbit Charge 2 in Investigating Daily Step and Sleep Data in Participants With Head and Neck Cancer Undergoing Radiation Therapy

Condition:   Head and Neck Carcinoma
Intervention:   Device: Monitoring Device
Sponsor:   Sidney Kimmel Cancer Center at Thomas Jefferson University
Not yet recruiting

https://ift.tt/2Ix9Mo4

In silico analysis of the potential mechanism of telocinobufagin on breast cancer MCF-7 cells

Publication date: Available online 5 April 2018
Source:Pathology - Research and Practice
Author(s): Yi-wu Dang, Peng Lin, Li-min Liu, Rong-quan He, Li-jie Zhang, Zhi-gang Peng, Xiao-jiao Li, Gang Chen
Backgrounds and aimsThe extractives from a ChanSu, traditional Chinese medicine, have been discovered to possess anti-inflammatory and tumor-suppressing abilities. However, the molecular mechanism of telocinobufagin, a compound extracted from ChanSu, on breast cancer cells has not been clarified. The aim of this study is to investigate the underlying mechanism of telocinobufagin on breast cancer cells.Methods and materialsThe differentially expressed genes after telocinobufagin treatment on breast cancer cells were searched and downloaded from Gene Expression Omnibus (GEO), ArrayExpress and literatures. Bioinformatics tools were applied to further explore the potential mechanism of telocinobufagin in breast cancer using the Kyoto Encyclopedia of genes and genomes (KEGG) pathway, Gene ontology (GO) enrichment, panther, and protein–protein interaction analyses. To better comprehend the role of telocinobufagin in breast cancer, we also queried the Connectivity Map using the gene expression profiles of telocinobufagin treatment.ResultsOne GEO accession (GSE85871) provided 1251 differentially expressed genes after telocinobufagin treatment on MCF-7 cells. The pathway of neuroactive ligand-receptor interaction, cell adhesion molecules (CAMs), intestinal immune network for IgA production, hematopoietic cell lineage and calcium signaling pathway were the key pathways from KEGG analysis. IGF1 and KSR1, Owning to higher protein levels in breast cancer tissues, IGF1 and KSR1 could be the hub genes related to telocinobufagin treatment. It was indicated that the molecular mechanism of telocinobufagin resembled that of fenspiride.ConclusionsTelocinobufagin might regulate neuroactive ligand-receptor interaction pathway to exert its influences in breast cancer MCF-7 cells, and its molecular mechanism might share some similarities with fenspiride. This study only presented a comprehensive picture of the role of telocinobufagin in breast cancer MCF-7 cells using big data. However, more thorough and deeper researches are required to add to the validity of this study.



https://ift.tt/2ErpUFi

STR1720, a potential sensitizer for radiotherapy and cytotoxicity effects of NVB-BEZ235 in metastatic breast cancer cells

Publication date: Available online 5 April 2018
Source:Pathology - Research and Practice
Author(s): Daryoush Fatehi, Amin Soltani, Mahdi Ghatrehsamani
BackgroundChemo-radio therapy (CRT) resistance is a main barrier in treating the triple negative breast cancer (TNBC). The success of conventional treatment may be ameliorated by elevating the responsiveness of the cancer cells to CRT. NVP-BEZ235 as a PI3K/AKT/mTOR dual inhibitor has been shown promising results in treating breast cancer cells. However, potential radiation-sensitizing effect of NVP-BEZ235 in TNBC remained unclear. In addition, SIRT-1 activation state and environmental cytokine were identified as being responsible for cancer cells responses to CRT. Herein, we investigate the role of interleukin 6 (IL-6) as a tumor environmental cytokine and SIRT1 in the effectiveness of NVP-BEZ235 plus radiotherapy.Material and methodsTNBC cells were pre-treated with/without IL-6 and were exposed to single and combination of SRT1720 (SIRT1 activator)/EX-527 (SIRT1 inhibitor) and/or NVP-BEZ235 and/or gamma radiation. The effect of our treatments on cellular growth was determined by MTT and the cellular death and CSCs percentage were determined by Flow cytometry. Senescence detection kit was used to assay the effect of our treatments on cellular senescence induction.ResultsActivation of SIRT1 via SRT1720 increased the efficacy of CRT in TNBC cells, especially when IL-6 exists in tumor microenvironment. Additionally, IL-6 pre-treatment followed by exposure to SRT1720 and NVP-BEZ235 significantly increased sensitivity of the cancer stem cells to radiation (p < 0.05).ConclusionOur result shows that combination of NVP-BEZ235 and SRT1720 may effectively improve late stage breast cancer cells therapeutics approach. Activation of SIRT1 and STAT3 in resistance breast cancer cells improve the in-vitro therapeutic efficacy of CRT.



https://ift.tt/2Jltapn

Clinical implications of TERT promoter mutation on IDH mutation and MGMT promoter methylation in diffuse gliomas

Publication date: Available online 5 April 2018
Source:Pathology - Research and Practice
Author(s): Hyun Sik Kim, Mi Jung Kwon, Joon Ho Song, Eun Soo Kim, Ho Young Kim, Kyueng-Whan Min
IDH mutation and MGMT promoter methylation are reliable prognostic and predictive biomarkers in grade II–IV diffuse gliomas. Recurrent mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene have also been found in diffuse gliomas. However, the prognostic and predictive effects of TERTp mutation on IDH or MGMT status are largely unknown.IDH1/2 and TERTp mutations, as well as MGMT methylation statuses, were examined via peptide nucleic acid-mediated PCR clamping and MGMT methylation-specific PCR in 67 paraffinized tumor samples, respectively.TERTp mutation was associated with older patients (≥60 years) and frontally located gliomas. Old age, frontal location, and grade IV were found to be predictive factors of TERTp mutation. TERTp mutation resulted in poor prognosis in overall diffuse gliomas. TERTp mutation was not correlated with overall survival (OS) or progression-free survival (PFS) in the diffuse gliomas. However, TERTp mutations, in combination with MGMT methylation or IDH mutation, showed that there were statistical significant survival differences between MGMT-unmethylated/TERTp-mutated and MGMT-unmethylated/TERTp-wildtype subgroups in grade II gliomas. There was a statistical significant survival difference of OS between IDH-wildtype/TERTp-mutated and IDH-mutated/TERTp-mutated subgroups in grade III gliomas. No significant associations between survival and MGMT/TERTp or IDH/TERTp status were found in grade IV gliomas. In conclusion, the combination of TERTp with IDH or MGMT status may be a prognostic indicator depending on grades.



https://ift.tt/2GCDPtH

Investigation of miR-136-5p key target genes and pathways in lung squamous cell cancer based on TCGA database and bioinformatics analysis

Publication date: Available online 5 April 2018
Source:Pathology - Research and Practice
Author(s): Zu-cheng Xie, Tian-tian Li, Bin-liang Gan, Xiang Gao, Li Gao, Gang Chen, Xiao-hua Hu
BackgroundLung squamous cell cancer (LUSC) is a common but challenging malignancy. It is important to illuminate the molecular mechanism of LUSC. Thus, we aim to explore the molecular mechanism of miR-136-5p in relation to LUSC.MethodsWe used the Cancer Genome Atlas (TCGA) database to investigate the expression of miR-136-5p in relation to LUSC. Then, we identified the possible miR-136-5p target genes through intersection of the predicted miR-136-5p target genes and LUSC upregulated genes from TCGA. Bioinformatics analysis was performed to determine the key miR-136-5p targets and pathways associated with LUSC. Finally, the expression of hub genes, correlation between miR-136-5p and hub genes, and expected significance of hub genes were evaluated via the TCGA and Genotype-Tissue Expression (GTEx) project.ResultsMiR-136-5p was significantly downregulated in LUSC patients. Glucuronidation, glucuronosyltransferase, and the retinoic acid metabolic process were the most enriched metabolic interactions in LUSC patients. Ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and retinol metabolism were identified as crucial pathways. Seven hub genes (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A10, SRD5A1, and ADH7) were found to be upregulated, and UGT1A1, UGT1A3, UGT1A6, UGT1A7, and ADH7 were negatively correlated with miR-136-5p. UGT1A7 and ADH7 were the most significantly involved miR-136-5p target genes, and high expression of these genes was correlated with better overall survival and disease-free survival of LUSC patients.ConclusionsDownregulated miR-136-5p may target UGT1A7 and ADH7 and participate in ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and retinol metabolism. High expression of UGT1A7 and ADH7 may indicate better prognosis of LUSC patients.



https://ift.tt/2JnEgKr

The effects of air pollution on daily cardiovascular diseases hospital admissions in Wuhan from 2013 to 2015

Publication date: June 2018
Source:Atmospheric Environment, Volume 182
Author(s): Xiaoying Wang, Wangcheng Wang, Shilin Jiao, Jing Yuan, Chunping Hu, Lin Wang
To evaluate the short-term effect of ambient air pollution on cardiovascular hospital admissions and capture the susceptible subpopulations in Wuhan, China, we adopted a generalized additive model to quantitatively analyze the influences of air pollutants on daily cardiovascular diseases hospital admissions and examine the influences of different subgroups. The largest significant effects for PM2.5, SO2 and NO2 on cardiovascular hospital admissions were observed at lag0, lag02 and lag02, respectively, and a 10μg/m³ increment in concentration of PM2.5, SO2 and NO2 were associated with 0.87% (95%CI: 0.05%–1.7%), 3.41% (95%CI: −0.21%-7.17%) and 2.98% (95%CI: 0.66%–5.37%) increases in cardiovascular hospital admissions. Nearly linear relationships were found for NO2 and PM2.5 with cardiovascular hospital admissions, and the J-shaped exposure-response relationship was observed for SO2 with cardiovascular hospital admissions. NO2 might have independent health effects of PM2.5 on the population at risk. The effect estimates for PM2.5 and SO2 were not sensitive with the inclusion of the co-pollutant adjustment. The gender, age and seasonal specific association between three pollutants and cardiovascular disease didn't show obvious differences in the magnitude and trend of the effects except that the seasonal difference of SO2 was significant. This study showed that PM2.5 and NO2 had effects on cardiovascular diseases, and the multiple pollutants should be considered together in the hazard models. In addition, the government should remind the resident to protect themselves and wear masks to avoid the harmful effect of air pollution, especially for the susceptible population.



https://ift.tt/2qaxwGX

Triplex DNA formation-mediated strand displacement reaction for highly sensitive fluorescent detection of melamine

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Xiaojuan Liu, Ningning Xu, Panpan Gai, Feng Li
Since melamine is a strong hazard to human health, the development of new methods for highly sensitive detection of melamine is highly desirable. Herein, a novel fluorescent biosensing strategy was designed for sensitive and selective melamine assay based on the recognition ability of abasic (AP) site in triplex towards melamine and signal amplification by Mg²⁺-dependent DNAzyme. In this strategy, the melamine-induced formation of triplex DNA was employed to trigger the strand displacement reaction (SDR). The SDR process converted the specific target recognition into the release and activation of Mg²⁺-dependent DNAzyme, which could catalyze the cleavage of fluorophore/quencher labeled DNA substrate (FQ), resulting in a significantly increased fluorescent signal. Under the optimal conditions, the fluorescent signal has a linear relationship with the logarithm of the melamine concentration in a wide range of 0.005–50 μM. The detection limit was estimated to be 0.9 nM (0.1ppb), which is sufficiently sensitive for practical application. Furthermore, this strategy exhibits high selectivity against other potential interfering substances, and the practical application of this strategy for milk samples reveals that the proposed strategy works well for melamine assay in real samples. Therefore, this strategy presents a new method for the sensitive melamine assay and holds great promise for sensing applications in the environment and the food safety field.

Graphical abstract

https://ift.tt/2Ix7lBW

In vivo monitoring of nicotine biosynthesis in tobacco leaves by low-temperature plasma mass spectrometry

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Sandra Martínez-Jarquín, Humberto Herrera-Ubaldo, Stefan de Folter, Robert Winkler
Low-temperature plasma (LTP) is capable of ionizing a broad range of organic molecules at ambient conditions. The coupling of LTP to a mass analyzer delivers chemical profiles from delicate objects. To investigate the suitability of LTP ionization for mass spectrometry (MS) based in vivo studies, we monitored the auxin-regulated nicotine biosynthesis in tobacco (Nicotiana tabacum) and evaluated possible biological effects. The measured nicotine concentrations in different experiments were comparable to literature data obtained with conventional methods. The observed compounds suggest the rupture of trichomes, and cell damage was observed on the spots exposed to LTP. However, the lesions only affected a negligible proportion of the leaf surface area and no systemic reaction was noted. Thus, our study provides the proof-of-concept for measuring the biosynthetic activity of plant surfaces in vivo.

Graphical abstract

Highlights

fx1


https://ift.tt/2JofEBo

Fabrication of RGO-NiCo2O4 nanorods composite from deep eutectic solvents for nonenzymatic amperometric sensing of glucose

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Yue Ni, Jian Xu, Hong Liu, Shijun Shao
A novel reduced graphene oxide supported nickel cobaltate nanorods composite (RGO-NiCo2O4) was prepared by a simple ionothermal method in deep eutectic solvents for the first time. Electrochemical results demonstrated that the obtained nanocomposite modified glassy carbon electrode exhibited excellent electrocatalytic performance towards the oxidation of glucose with a wide double-linear range from 1 μM to 25 mM and a low detection limit of 0.35 μM (S/N = 3). NiCo2O4 nanorods with many small interconnected nanoparticles provided many electrocatalytic active sites, while RGO with large surface area offered good electrical conductivity. The synergistic effect between NiCo2O4 nanorods and RGO contributed to the enhanced sensing ability of the hybrid nanostructure. This sensitive glucose sensor can be also used for the practical detection of glucose in human serum.

Graphical abstract

https://ift.tt/2uMZeze

Evaporative fluorophore labeling of carbohydrates via reductive amination

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Balazs Reider, Marton Szigeti, Andras Guttman
As analytical glycomics became to prominence, newer and more efficient sample preparation methods are being developed. Albeit, numerous reductive amination based carbohydrate labeling protocols have been reported in the literature, the preferred way to conduct the reaction is in closed vials. Here we report on a novel evaporative labeling protocol with the great advantage of continuously concentrating the reagents during the tagging reaction, therefore accommodating to reach the optimal reagent concentrations for a wide range of glycan structures in a complex mixture. The optimized conditions of the evaporative labeling process minimized sialylation loss, otherwise representing a major issue in reductive amination based carbohydrate tagging. In addition, complete and uniform dispersion of dry samples was obtained by supplementing the low volume labeling mixtures (several microliters) with the addition of extra solvent (e.g., THF). Evaporative labeling is an automation-friendly glycan labeling method, suitable for standard open 96 well plate format operation.

Graphical abstract

https://ift.tt/2JkyCZs

Sequential injection system with in-line solid phase extraction and soil mini-column for determination of zinc and copper in soil leachates

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Justyna Paluch, Raquel B.R. Mesquita, Víctor Cerdà, Joanna Kozak, Marcin Wieczorek, António O.S.S. Rangel
A sequential injection (SI) system equipped with in-line solid phase extraction column and in-line soil mini-column is proposed for determination of zinc and copper in soil leachates. The spectrophotometric determination (560 nm) is based on the reaction of both analytes with 1-(2-Pyridylazo)-2-naphthol (PAN). Zinc is determined after retaining copper on a cationic resin (Chelex100) whereas copper is determined from the difference of the absorbance measured for both analytes, introduced into the system with the use of a different channel, and zinc absorbance. The influence of several potential interferences was studied. Using the developed method, zinc and copper were determined within the concentration ranges of 0.005–0.300 and 0.011–0.200 mg L⁻¹, and with a relative standard deviation lower than 6.0% and 5.1%, respectively. The detection limits are 1.4 and 3.0 µg/L for determination of zinc and copper, respectively. The developed SI method was verified by the determination of both analytes in synthetic and certified reference materials of water samples, and applied to the determination of the analytes in rain water and soil leachates from laboratory scale soil core column and in-line soil mini-column.

Graphical abstract

https://ift.tt/2Ivp7W4

Polarity tuned perphenylcarbamoylated cyclodextrin separation materials for achiral and chiral differentiation

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Xiaoxuan Li, Jia Li, Qing Kang, Yong Wang
Phenylcarbamoyls are known to remarkably accentuate cyclodextrin's enantioselectivities. In this work, by inducing electron-donating methoxyl or electron-withdrawing bromine/trifluoromethyl moieties, three novel cyclodextrin enantioseparation materials including per(4-trifluoromethoxy) phenylcarbamoylated-β-CD CSP (CSP1), per(4-bromo)phenylcarbamoylated-β-CD CSP (CSP2) and per(4-methoxy)phenylcarbamoylated-β-CD CSP (CSP3) were prepared via thiol-ene click chemistry. The polarity tuning decorations are found to significantly influence the CSPs' achiral and chiral separation performance. The three CSPs can easily separate toluene, 1,2-xylene and 1,3,5-trimethylbenzene with the strongest retention on CSP3. In reversed-phase mode, the three CSPs exhibited completely different enantioseparation ability towards specific isoxazolines and flavonoids. 4′-hydroxyflavanone was separated on CSP1 with a resolution of 9.24 while 6-methoxyflavanone was best separated on CSP2 (Rs = 9.98). CSP3 exhibited the strongest differentiation ability towards 4NPh-2Py (Rs = 9.69). The comparison study may provide some insight into the design of functional cyclodextrin materials.

Graphical abstract

https://ift.tt/2Jop8fZ

Smart bi-metallic perovskite nanofibers as selective and reusable sensors of nano-level concentrations of non-steroidal anti-inflammatory drugs

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Mona A. Mohamed, Menna M. Hasan, Ibrahim H. Abdullah, Ahmed M. Abdellah, Ali M. Yehia, Nashaat Ahmed, Walaa Abbas, Nageh K. Allam
A strategy for trace-level carbon-based electrochemical sensors is investigated via exploring the interesting properties of BaNb2O6 nanofibers (NFs). Utilizing adsorptive stripping square wave voltammetry (ASSWV), an electrochemical sensing platform was developed based on BaNb2O6 nanofibers-modified carbon paste electrode (CPE) for the sensitive detection of lornoxicam (LOR). Different techniques were used to characterize the fabricated BaNb2O6 perovskite NFs. The obtained data show the feasibility to electro-oxidize LOR and paracetamol (PAR) on the surface of the fabricated sensor. The amount of nanofiber and testing conditions were optimized using response surface methodology and ASSWV technique. The optimized BaNb2O6/CPE sensor exhibits low detection limit of 6.39 × 10⁻¹⁰ mol L⁻¹, even in the presence of the co-formulated drug paracetamol (PAR). The sensor was successfully applied for biological applications.

Graphical abstract

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A colorimetric and turn-on NIR fluorescent probe based on xanthene system for sensitive detection of thiophenol and its application in bioimaging

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Shao-Hua Guo, Tao-Hua Leng, Kai Wang, Cheng-Yun Wang, Yong-Jia Shen, Wei-Hong Zhu
Developing fluorescent probes for specific detection of extremely toxic thiophenols is pretty significant in the field of environment, chemistry and biology. We report herein a turn-on red fluorescent xanthene-based probe (RD-Probe) for detecting thiophenol with high selectivity over other analytes including aliphatic thiols. The probe could play the part of a "naked-eye"colorimetric indicator toward thiophenol. Moreover, the relative fluorescence intensity at 653 nm displayed good linearity with the concentration of thiophenol ranging from 0 to 6 μM, and the limit of detection for thiophenol could be as low as 15 nM. Furthermore, the practicability of RD-Probe has been successfully proved through the quantitative thiophenol detection in real water samples and fluorescence bioimaging of thiophenol in HeLa cells.

Graphical abstract

https://ift.tt/2q9d9e8

Study of chromium species release from metal implants in blood and joint effusion: Utilization of HPLC-ICP-MS

Publication date: 1 August 2018
Source:Talanta, Volume 185
Author(s): Radka Pechancova, Tomáš Pluháček, Jiří Gallo, David Milde
The objective of this study was to develop and validate a novel analytical procedure for determination of total chromium and Cr(III) and Cr(VI) species released from metal implants into whole blood and joint effusion. Firstly, the ion-pair chromatographic method employing reversed-phase high-performance liquid chromatography inductively coupled plasma mass spektrometry (ICP-MS) for analysis of species was developed. Secondly, all samples, protein and low molecular fractions were analyzed for their total chromium content using ICP-MS. This new measurement procedure was validated by the following parameters: limit of detection (0.13 μg L^-1 for Cr(III), 0.14 μg L^-1 for Cr(VI)), linearity of calibration, trueness (recovery 84–92%), intermediate precision (RSD < 5%). We determined statistically significantly higher chromium levels in joint effusion samples obtained from patients in comparison with a control group. On the other hand, no relevant difference among the concentrations of both species and total chromium in blood was observed. Our results show that the majority of chromium is present in the trivalent form and bound to proteins. This speciation study is rare in the field of speciation analysis in clinical samples. It is characterized by very fast and simple sample preparation without any changes in distribution or stability of bTWSToth Cr forms and efficient simultaneous analysis of Cr species.

Graphical abstract

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The Acute Treatment of Methemoglobinemia in Pregnancy

Publication date: Available online 5 April 2018
Source:The Journal of Emergency Medicine
Author(s): Nels Grauman Neander, Carly A. Loner, Jason M. Rotoli
BackgroundMethemoglobinemia can be a potentially lethal condition due to the hypoxic stress placed on the body. In pregnancy, the deleterious effects can be even more catastrophic. The benefits of treatment in all patients, especially in those who are pregnant, must outweigh the inherent risks of the therapies used to treat methemoglobinemia.Case ReportWe present a case of a 26-year-old Hispanic pregnant female at 30 weeks gestation presenting to the emergency department for chest pain, hypoxia, and cyanosis. She was subsequently diagnosed with methemoglobinemia, treated with methylene blue, and admitted to the intensive care unit with toxicology and obstetrics consultations. As an outpatient, the patient underwent genetic testing and was diagnosed with homozygous cytochrome b5 reductase deficiency as the etiology of the methemoglobinemia.Why Should an Emergency Physician Be Aware of This?Methemoglobinemia is a rare, potentially lethal, but treatable condition. In the setting of pregnancy, methemoglobinemia can pose a significant risk to the mother and fetus by causing acute hypoxia. Because methemoglobinemia can be acquired or congenital, treatments vary based on the etiology. Methylene blue is the mainstay treatment for symptomatic methemoglobinemia of levels > 20%. The teratogenic risks of methylene blue require risk−benefit analysis and discussion with the patient before utilization. Systemic maternal administration is theorized to be of lowest risk to the fetus. In this case, methylene blue was used safely as an emergent therapy for congenital methemoglobinemia during pregnancy.



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Bedside Ultrasound Diagnosis of Complete Achilles Tendon Tear in a 25-Year-Old Man with Calf Injury

Publication date: Available online 5 April 2018
Source:The Journal of Emergency Medicine
Author(s): Mitchell Odom, Nathan Haas, Kylee Phillips




https://ift.tt/2qb7fZf

The Two-Bag Method for Treatment of Diabetic Ketoacidosis in Adults

Publication date: Available online 5 April 2018
Source:The Journal of Emergency Medicine
Author(s): Nathan L. Haas, Roma Y. Gianchandani, Kyle J. Gunnerson, Benjamin S. Bassin, Arun Ganti, Christopher Hapner, Caryn Boyd, James A. Cranford, Sage P. Whitmore
BackgroundThe "two-bag method" of management of diabetic ketoacidosis (DKA) allows for titration of dextrose delivery by adjusting the infusions of two i.v. fluid bags of varying dextrose concentrations while keeping fluid, electrolyte, and insulin infusion rates constant.ObjectiveWe aimed to evaluate the feasibility and potential benefits of this strategy in adult emergency department (ED) patients with DKA.MethodsThis is a before-and-after comparison of a protocol using the two-bag method operationalized in our adult ED in 2015. A retrospective electronic medical record search identified adult ED patients presenting with DKA from January 1, 2013 to June 30, 2016. Clinical and laboratory data, timing of medical therapies, and safety outcomes were collected and analyzed.ResultsSixty-eight patients managed with the two-bag method (2B) and 107 patients managed with the one-bag method (1B) were identified. The 2B and 1B groups were similar in demographics and baseline metabolic derangements, though significantly more patients in the 2B group received care in a hybrid ED and intensive care unit setting (94.1% vs. 51.4%; p < 0.01). 2B patients experienced a shorter interval to first serum bicarbonate ≥ 18 mEq/L (13.4 vs. 20.0 h; p < 0.05), shorter duration of insulin infusion (14.1 vs. 21.8 h; p < 0.05), and fewer fluid bags were charged to the patient (5.2 vs. 29.7; p < 0.01). Frequency of any measured hypoglycemia or hypokalemia trended in favor of the 2B group (2.9% vs. 10.3%; p = 0.07; 16.2% vs. 27.1%; p = 0.09; respectively), though did not reach significance.ConclusionsThe 2B method appears feasible for management of adult ED patients with DKA, and use was associated with earlier correction of acidosis, earlier discontinuation of insulin infusion, and fewer i.v. fluid bags charged than traditional 1B methods, while no safety concerns were observed.



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Recurrent Ethylene Glycol Poisoning with Elevated Lactate Levels to Obtain Opioid Medications

Publication date: Available online 5 April 2018
Source:The Journal of Emergency Medicine
Author(s): Matthew Zuckerman, Tim Vo
BackgroundMalingering is when a patient feigns illness for secondary gain. While most patients with malingering manufacture or exaggerate symptoms, some patients may induce illness. Previous reports of malingering patients inducing illness include sepsis, kidney pain, migraine, and chest pain. However, acute poisoning as a manifestation of malingering appears to be rare.Case ReportWe describe the case of a 39-year-old man who presented to the emergency department complaining of diffuse body pain. The patient reported multiple admission at outside hospitals for "lactate" and said, "it feels like it is happening again because of how my body feels." Laboratory findings were concerning for serum lactate of >20.0 mmol/L and ethylene glycol (EG) level of 19 mg/dL. A chart review found that the man had been admitted for elevated serum lactate 8 times to area hospitals in several years, often in the setting of EG poisoning. During these episodes he required intravenous fluids and frequent intravenous pain medications. When confronted about concern regarding the recurrent fallacious lactate levels in the setting of factitious EG ingestion, the patient often became combative and left against medical advice. The primary metabolite of EG, glycolic acid, can interfere with lactate assays, causing a false elevation. Our patient apparently recognized this and took advantage of it to be admitted and receive intravenous opioids. This is the only case known to us of malingering via EG ingestion.Why Should an Emergency Physician be Aware of This?Emergency physicians should be aware that metabolites of EG may interfere with serum lactate assay. In addition, they should be aware of possible malingering-related poisoning and plausible association with requests for intravenous opioid pain medications. This represents a risk to the patient and others if undiagnosed.



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Effect of heat on soil seedbank of three contrasting physiognomies in Shasha forest reserve, Southwestern Nigeria

Publication date: Available online 5 April 2018
Source:Acta Oecologica
Author(s): D.S. Akinyemi, S.R. Oseni, S.O. Oke
The effects of soil heating which usually occur during forest fires on the floristic composition and seed density of the soil seed bank of Shasha forest reserve in Southwestern Nigeria was investigated and the potential of the soil seedbank in forest restoration process (especially after a fire) was examined. Three distinct sites (Regrowth forest, Gmelina and Pinus plantations) were selected in the forest reserve. Species enumeration, identification and distribution into families of the standing vegetation were carried out. Soil samples were collected at 0–15 cm depth from each plot in March 2012. One set of replicate samples was heated in an oven until the soil reached 80 °C (to simulate typical temperature at soil surface during forest fires) while the other serves as a control. They were subjected to seedling emergence for six months to determine the density and species composition of the seed banks of the study sites. Seedling emergence result for heated and unheated soil samples showed that the seedbank density was higher in control than heated samples in the three sites. Few woody species emerged from the soil seedbank of three study sites and in both control and heated samples. There was a significant difference in total seed density when treatments were compared (P < 0.05) and no significant difference (P > 0.05) when sites were compared. Diversity and evenness indices follow the order Regrowth forest > Pinus plantation > Gmelina plantation. NMDS (non-metric multi-dimensional scaling) ordination revealed low similarity in the species composition of extant vegetation and seedbank. The potential of vegetation restoration of the disturbed forest reserve from seed bank is limited, and heat from fire had negative effects on the seed bank characteristics of the forest but selectively enhanced the emergence of species like Pinus carribaea.



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Are species photosynthetic characteristics good predictors of seedling post-hurricane demographic patterns and species spatiotemporal distribution in a hurricane impacted wet montane forest?

Publication date: May 2018
Source:Acta Oecologica, Volume 89
Author(s): Denneko Luke, Kurt McLaren
In situ measurements of leaf level photosynthetic response to light were collected from seedlings of ten tree species from a tropical montane wet forest, the John Crow Mountains, Jamaica. A model-based recursive partitioning ('mob') algorithm was then used to identify species associations based on their fitted photosynthetic response curves. Leaf area dark respiration (RD) and light saturated maximum photosynthetic (Amax) rates were also used as 'mob' partitioning variables, to identify species associations based on seedling demographic patterns (from June 2007 to May 2010) following a hurricane (Aug. 2007) and the spatiotemporal distribution patterns of stems in 2006 and 2012. RD and Amax rates ranged from 1.14 to 2.02 μmol (CO2) m⁻²s⁻¹ and 2.97–5.87 μmol (CO2) m⁻²s⁻¹, respectively, placing the ten species in the range of intermediate shade tolerance. Several parsimonious species 'mob' groups were formed based on 1) interspecific differences among species response curves, 2) variations in post-hurricane seedling demographic trends and 3) RD rates and species spatiotemporal distribution patterns at aspects that are more or less exposed to hurricanes. The composition of parsimonious groupings based on photosynthetic curves was not concordant with the groups based on demographic trends but was partially concordant with the RD - species spatiotemporal distribution groups. Our results indicated that the influence of photosynthetic characteristics on demographic traits and species distributions was not straightforward. Rather, there was a complex pattern of interaction between ecophysiological and demographic traits, which determined species successional status, post-hurricane response and ultimately, species distribution at our study site.



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Dataset from the dynamic shake-table test of a full-scale unreinforced clay-masonry building with flexible timber diaphragms

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Stylianos Kallioras, Gabriele Guerrini, Umberto Tomassetti, Simone Peloso, Francesco Graziotti
This paper provides information related to the sensor measurements obtained from an unreinforced masonry building subjected to incremental dynamic shake-table tests at the EUCENTRE facilities in Pavia, Italy. These tests provide a unique data set that captures at full scale the in-plane and out-of-plane behavior of unreinforced masonry walls, and the influence of flexible diaphragms on the dynamic global response of a complete building. The authors made this information available to assist in the development of analytical and numerical models, necessary to estimate the dynamic response and the engineering parameters for the performance-based seismic assessment of unreinforced masonry buildings. All recorded data (acceleration and displacement time histories) and the videos of the tests can be requested online on the EUCENTRE repository at the URL https://ift.tt/2q9LRDz referring to EUC-BUILD-2. For further interpretation of the sensor recordings, and for a detailed discussion on the seismic performance of the building specimen, the reader is referred to the article entitled "Experimental seismic performance of a full-scale unreinforced clay-masonry building with flexible timber diaphragms" (Kallioras et al., 2018) [1].



https://ift.tt/2GCsI8a

Transcriptome data of Prorocentrum donghaiense Lu under nitrogen and phosphorus limitation

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Jing-Jing Li, Wei Xia, Hong-Po Dong, Lin-Jian Ou
Prorocentrum donghaiense Lu is one of the most frequently occurred harmful algae in the coastal waters of China. The growth of P. donghaiense can be limited by nitrogen or phosphorus in marine environment. However, molecular mechanism of P. donghaiense in response to nitrogen and phosphorus limitation is poorly understood. In this study, we summarized the transcriptome datasets of P. donghaiense in response to nitrogen or phosphorus depletion. Raw data of approximately 19 GB in size were generated from IlluminaHiSeq^TM 4000 sequencer. From 250, 539, 604 raw reads, 211, 394, 052 clean reads were obtained. The raw data were deposited into SRA database with the BioProject ID 436946. Our dataset will provide more scientific and valuable information for analyses of gene expression related to metabolic processes in P. donghaiense.



https://ift.tt/2GC50sZ

The collection of images of an insulator taken outdoors in varying lighting conditions with additional laser spots

Publication date: June 2018
Source:Data in Brief, Volume 18
Author(s): Michał Tomaszewski, Bogdan Ruszczak, Paweł Michalski
Electrical insulators are elements of power lines that require periodical diagnostics. Due to their location on the components of high-voltage power lines, their imaging can be cumbersome and time-consuming, especially under varying lighting conditions.Insulator diagnostics with the use of visual methods may require localizing insulators in the scene. Studies focused on insulator localization in the scene apply a number of methods, including: texture analysis, MRF (Markov Random Field), Gabor filters or GLCM (Gray Level Co-Occurrence Matrix) [1,2]. Some methods, e.g. those which localize insulators based on colour analysis [3], rely on object and scene illumination, which is why the images from the dataset are taken under varying lighting conditions. The dataset may also be used to compare the effectiveness of different methods of localizing insulators in images.This article presents high-resolution images depicting a long rod electrical insulator under varying lighting conditions and against different backgrounds: crops, forest and grass. The dataset contains images with visible laser spots (generated by a device emitting light at the wavelength of 532 nm) and images without such spots, as well as complementary data concerning the illumination level and insulator position in the scene, the number of registered laser spots, and their coordinates in the image. The laser spots may be used to support object-localizing algorithms, while the images without spots may serve as a source of information for those algorithms which do not need spots to localize an insulator.



https://ift.tt/2q9mv8U

Different relationships between personal exposure and ambient concentration by particle size

Abstract

Ambient particulate matter (PM) concentrations at monitoring stations were often used as an indicator of population exposure to PM in epidemiological studies. The correlation between personal exposure and ambient concentrations of PM varied because of diverse time-activity patterns. The aim of this study was to determine the relationship between personal exposure and ambient concentrations of PM₁₀ and PM_2.5 with minimal impact of time-activity pattern on personal exposure. Performance of the MicroPEM, v3.2 was evaluated by collocation with central ambient air monitors for PM₁₀ and PM_2.5. A field technician repeatedly conducted measurement of 24 h personal exposures to PM₁₀ and PM_2.5 with a fixed time-activity pattern of office worker over 26 days in Seoul, Korea. The relationship between the MicroPEM and the ambient air monitor showed good linearity. Personal exposure and ambient concentrations of PM_2.5 were highly correlated with a fixed time-activity pattern compared with PM₁₀. The finding implied a high infiltration rate of PM_2.5 and low infiltration rate of PM₁₀. The relationship between personal exposure and ambient concentrations of PM₁₀ and PM_2.5 was different for high level episodes. In the Asian dust episode, staying indoors could reduce personal exposure to PM₁₀. However, personal exposure to PM_2.5 could not be reduced by staying indoors during the fine dust advisory episode.

https://ift.tt/2H3pbz8

The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES

Abstract

Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration.

https://ift.tt/2uPv4v5

Hybrid Capture‐Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in BRCA1‐Mutant Cholangiocarcinoma Harboring a Novel YWHAZ‐BRAF Fusion

AbstractBiliary tract cancers such as cholangiocarcinoma represent a heterogeneous group of cancers that can be difficult to diagnose. Recent comprehensive genomic analyses in large cholangiocarcinoma cohorts have defined important molecular subgroups within cholangiocarcinoma that may relate to anatomic location and etiology [1–4] and may predict responsiveness to targeted therapies in development [5–7]. These emerging data highlight the potential for tumor genomics to inform diagnosis and treatment options in this challenging tumor type. We report the case of a patient with a germline BRCA1 mutation who presented with a cholangiocarcinoma driven by the novel YWHAZ‐BRAF fusion. Hybrid capture‐based DNA sequencing and copy number analysis performed as part of clinical care demonstrated that two later‐occurring tumors were clonally derived from the primary cholangiocarcinoma rather than distinct new primaries, revealing an unusual pattern of late metachronous metastasis. We discuss the clinical significance of these genetic alterations and their relevance to therapeutic strategies.Key Points. Hybrid capture‐based next‐generation DNA sequencing assays can provide diagnostic clarity in patients with unusual patterns of metastasis and recurrence in which the pathologic diagnosis is ambiguous.To our knowledge, this is the first reported case of a YWHAZ‐BRAF fusion in pancreaticobiliary cancer, and a very rare case of cholangiocarcinoma in the setting of a germline BRCA1 mutation.The patient's BRCA1 mutation and YWHAZ‐BRAF fusion constitute potential targets for future therapy.

https://ift.tt/2EkAjCx

The Role of Notch3 in Cancer

AbstractThe Notch family is a highly conserved gene group that regulates cell‐cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue‐specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling.Implications for Practice.The Notch family is a highly conserved gene group that regulates cell‐cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity.

https://ift.tt/2HcaeIK

Comprehensive Computed Tomography Radiomics Analysis of Lung Adenocarcinoma for Prognostication

AbstractBackground.In this era of personalized medicine, there is an expanded demand for advanced imaging biomarkers that reflect the biology of the whole tumor. Therefore, we investigated a large number of computed tomography‐derived radiomics features along with demographics and pathology‐related variables in patients with lung adenocarcinoma, correlating them with overall survival.Materials and Methods.Three hundred thirty‐nine patients who underwent operation for lung adenocarcinoma were included. Analysis was performed using 161 radiomics features, demographic, and pathologic variables and correlated each with patient survival. Prognostic performance for survival was compared among three models: (a) using only clinicopathological data; (b) using only selected radiomics features; and (c) using both clinicopathological data and selected radiomics features.Results.At multivariate analysis, age, pN, tumor size, type of operation, histologic grade, maximum value of the outer 1/3 of the tumor, and size zone variance were statistically significant variables. In particular, maximum value of outer 1/3 of the tumor reflected tumor microenvironment, and size zone variance represented intratumor heterogeneity. Integration of 31 selected radiomics features with clinicopathological variables led to better discrimination performance.Conclusion.Radiomics approach in lung adenocarcinoma enables utilization of the full potential of medical imaging and has potential to improve prognosis assessment in clinical oncology.Implications for Practice.Two radiomics features were prognostic for lung cancer survival at multivariate analysis: (a) maximum value of the outer one third of the tumor reflects the tumor microenvironment and (b) size zone variance represents the intratumor heterogeneity. Therefore, a radiomics approach in lung adenocarcinoma enables utilization of the full potential of medical imaging and could play a larger role in clinical oncology.

https://ift.tt/2uOxiuF

Value of Supportive Care Pharmacogenomics in Oncology Practice

AbstractGenomic medicine provides opportunities to personalize cancer therapy for an individual patient. Although novel targeted therapies prolong survival, most patients with cancer continue to suffer from burdensome symptoms including pain, depression, neuropathy, nausea and vomiting, and infections, which significantly impair quality of life. Suboptimal management of these symptoms can negatively affect response to cancer treatment and overall prognosis. The effect of genetic variation on drug response—otherwise known as pharmacogenomics—is well documented and directly influences an individual patient's response to antiemetics, opioids, neuromodulators, antidepressants, antifungals, and more. The growing body of pharmacogenomic data can now guide clinicians to select the safest and most effective supportive medications for an individual patient with cancer from the very first prescription. This review outlines a theoretical patient case and the implications of using pharmacogenetic test results to personalize supportive care throughout the cancer care continuum.Implications for Practice.Integration of palliative medicine into the cancer care continuum has resulted in increased quality of life and survival for patients with many cancer types. However, suboptimal management of symptoms such as pain, neuropathy, depression, and nausea and vomiting continues to place a heavy burden on patients with cancer. As demonstrated in this theoretical case, pharmacogenomics can have a major effect on clinical response to medications used to treat these conditions. Recognizing the value of supportive care pharmacogenomics in oncology and application into routine practice offers an objective choice for the safest and most effective treatment compared with the traditional trial and error method.

https://ift.tt/2HcYEx4

FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome

AbstractOn August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life‐threatening chimeric antigen receptor (CAR) T cell‐induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE‐C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life‐threatening CRS; only the first episode of CRS was included in the analysis. The efficacy population for the CTL019 cohort included 24 male and 21 female patients (total 45 patients) of median age 12 years. The median time from the start of CRS to the first dose of tocilizumab was 4 days (range, 0–18 days). Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty‐one patients (69%; 95% confidence interval, 53%–82%) achieved a response as defined. In an independent cohort of 15 patients with KTE‐C19‐induced CRS, 53% responded. Further study is needed to determine the optimal dose of tocilizumab and to confirm the safety of its use for treatment of patients with CAR T cell‐induced CRS.Implications for Practice.Severe or life‐threatening chimeric antigen receptor (CAR) T cell‐induced cytokine release syndrome (CRS) requires urgent treatment to prevent fatal outcomes. In two independent cohorts, the majority of patients with severe or life‐threatening CAR T cell‐induced CRS responded to treatment with one or two doses of tocilizumab in addition to advanced supportive care. More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell‐induced CRS.

https://ift.tt/2EnJNwP

Editorial Board

Publication date: April 2018
Source:Nano Today, Volume 19





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Feature Selection for the Classification of Traced Neurons

Publication date: Available online 5 April 2018
Source:Journal of Neuroscience Methods
Author(s): José D. López-Cabrera, Juan V. Lorenzo-Ginori
BackgroundThe great availability of computational tools to calculate the properties of traced neurons leads to the existence of many descriptors which allow the automated classification of neurons from these reconstructions. This situation determines the necessity to eliminate irrelevant features as well as making a selection of the most appropriate among them, in order to improve the quality of the classification obtained.MethodsThe dataset used contains a total of 318 traced neurons, classified by human experts in 192 GABAergic interneurons and 126 pyramidal cells. The features were extracted by means of the L-measure software, which is one of the most used computational tools in neuroinformatics to quantify traced neurons. We review some current feature selection techniques as filter, wrapper, embedded and ensemble methods. The stability of the feature selection methods was measured. For the ensemble methods, several aggregation methods based on different metrics were applied to combine the subsets obtained during the feature selection process.ResultsThe subsets obtained applying feature selection methods were evaluated using supervised classifiers, among which Random Forest, C4.5, SVM, Naïve Bayes, Knn, Decision Table and the Logistic classifier were used as classification algorithms.Comparison with Existing MethodsFeature selection methods of types filter, embedded, wrappers and ensembles were compared and the subsets returned were tested in classification tasks for different classification algorithms.ConclusionsL-measure features EucDistanceSD, PathDistanceSD, Branch_pathlengthAve, Branch_pathlengthSD and EucDistanceAve were present in more than 60% of the selected subsets which provides evidence about their importance in the classification of this neurons.



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Meetings Calendar 2018

Rejuvenation Research, Ahead of Print.


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Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Eesha Sharma, Benjamin J. Blencowe
The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.

Teaser

The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.


https://ift.tt/2EmgJ95

Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Sree Deepthi Muthukrishnan, Alvaro G. Alvarado, Harley I. Kornblum
Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression.

Teaser

Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression.


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To Be Young at Heart

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Patrick C.H. Hsieh, Timothy J. Kamp
Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure.

Teaser

Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure.


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The Rules of Successful Speed Dating Are Complex, Even for Super-Enhancers

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Raymond Poot
Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.

Teaser

Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.


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Sending Cancer into the Fetal Position

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Hannah A. Pizzato, Deepta Bhattacharya
Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers.

Teaser

Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers.


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De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Ayana Sawai, Jeremy S. Dasen
DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.

Teaser

DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.


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Mentoring the Next Generation: Fiona Watt

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Fiona Watt about her views.



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Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Loukia Yiangou, Alexander D.B. Ross, Kim Jee Goh, Ludovic Vallier
The liver, lung, pancreas, and digestive tract all originate from the endoderm germ layer, and these vital organs are subject to many life-threatening diseases affecting millions of patients. However, primary cells from endodermal organs are often difficult to grow in vitro. Human pluripotent stem cells thus hold great promise for generating endoderm cells and their derivatives as tools for the development of new therapeutics against a variety of global healthcare challenges. Here we describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy.

Teaser

In this Protocol Review, Yiangou et al. describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy.


https://ift.tt/2GVGjXB

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Xiuxing Wang, Briana C. Prager, Qiulian Wu, Leo J.Y. Kim, Ryan C. Gimple, Yu Shi, Kailin Yang, Andrew R. Morton, Wenchao Zhou, Zhe Zhu, Elisabeth Anne Adanma Obara, Tyler E. Miller, Anne Song, Sisi Lai, Christopher G. Hubert, Xun Jin, Zhi Huang, Xiaoguang Fang, Deobrat Dixit, Weiwei Tao, Kui Zhai, Cong Chen, Zhen Dong, Guoxin Zhang, Stephen M. Dombrowski, Petra Hamerlik, Stephen C. Mack, Shideng Bao, Jeremy N. Rich
Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.

Graphical abstract

Teaser

Wang et al. investigate reciprocal signaling between glioma stem cells and their differentiated glioblastoma cell progeny. The authors demonstrate that differentiated tumor cells promote the glioblastoma hierarchy and tumor growth through a paracrine feedback loop of neurotrophin signaling in cooperation with stem cell-like tumor cells.


https://ift.tt/2EnRRNW

Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Shangtao Cao, Shengyong Yu, Dongwei Li, Jing Ye, Xuejie Yang, Chen Li, Xiaoshan Wang, Yuanbang Mai, Yue Qin, Jian Wu, Jiangping He, Chunhua Zhou, He Liu, Bentian Zhao, Xiaodong Shu, Chuman Wu, Ruiping Chen, Waiyee Chan, Guangjin Pan, Jiekai Chen, Jing Liu, Duanqing Pei
Despite its exciting potential, chemical induction of pluripotency (CIP) efficiency remains low and the mechanisms are poorly understood. We report the development of an efficient two-step serum- and replating-free CIP protocol and the associated chromatin accessibility dynamics (CAD) by assay for transposase-accessible chromatin (ATAC)-seq. CIP reorganizes the somatic genome to an intermediate state that is resolved under 2iL condition by re-closing previously opened loci prior to pluripotency acquisition with gradual opening of loci enriched with motifs for the OCT/SOX/KLF families. Bromodeoxyuridine, a critical ingredient of CIP, is responsible for both closing and opening critical loci, at least in part by preventing the opening of loci enriched with motifs for the AP1 family and facilitating the opening of loci enriched with SOX/KLF/GATA motifs. These changes differ markedly from CAD observed during Yamanaka-factor-driven reprogramming. Our study provides insights into small-molecule-based reprogramming mechanisms and reorganization of nuclear architecture associated with cell-fate decisions.

Graphical abstract

Teaser

Cao et al. report an efficient protocol for chemical induction of pluripotency and its chromatin accessibility dynamics, which links small molecules and the reorganization of nuclear architecture in the context of cell-fate decisions.


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Coordinated Control of mRNA and rRNA Processing Controls Embryonic Stem Cell Pluripotency and Differentiation

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Nina S. Corsini, Angela M. Peer, Paul Moeseneder, Mykola Roiuk, Thomas R. Burkard, Hans-Christian Theussl, Isabella Moll, Juergen A. Knoblich
Stem cell-specific transcriptional networks are well known to control pluripotency, but constitutive cellular processes such as mRNA splicing and protein synthesis can add complex layers of regulation with poorly understood effects on cell-fate decisions. Here, we show that the RNA binding protein HTATSF1 controls embryonic stem cell differentiation by regulating multiple aspects of RNA processing during ribosome biogenesis. HTATSF1, in a complex with splicing factor SF3B1, controls intron removal from ribosomal protein transcripts and regulates ribosomal RNA transcription and processing, thereby controlling 60S ribosomal abundance and protein synthesis. HTATSF1-dependent protein synthesis is essential for naive pre-implantation epiblast to transition into post-implantation epiblast, a stage with transiently low protein synthesis, and further differentiation toward neuroectoderm. Together, these results identify coordinated regulation of ribosomal RNA and protein synthesis by HTATSF1 and show that this essential mechanism controls protein synthesis during early mammalian embryogenesis.

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Teaser

Corsini et al. identify the splicing factor HTATSF1 as a regulator of intron retention specifically in ribosomal proteins and of ribosomal RNA transcription and processing to modulate levels of overall protein synthesis. They further demonstrate that HTATSF1-mediated protein synthesis dynamics control embryonic stem cell pluripotency and neuroectoderm differentiation.


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A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Marcella Cesana, Michael H. Guo, Davide Cacchiarelli, Lara Wahlster, Jessica Barragan, Sergei Doulatov, Linda T. Vo, Beatrice Salvatori, Cole Trapnell, Kendell Clement, Patrick Cahan, Kaloyan M. Tsanov, Patricia M. Sousa, Barbara Tazon-Vega, Adriano Bolondi, Federico M. Giorgi, Andrea Califano, John L. Rinn, Alexander Meissner, Joel N. Hirschhorn, George Q. Daley
While gene expression dynamics have been extensively cataloged during hematopoietic differentiation in the adult, less is known about transcriptome diversity of human hematopoietic stem cells (HSCs) during development. To characterize transcriptional and post-transcriptional changes in HSCs during development, we leveraged high-throughput genomic approaches to profile miRNAs, lincRNAs, and mRNAs. Our findings indicate that HSCs manifest distinct alternative splicing patterns in key hematopoietic regulators. Detailed analysis of the splicing dynamics and function of one such regulator, HMGA2, identified an alternative isoform that escapes miRNA-mediated targeting. We further identified the splicing kinase CLK3 that, by regulating HMGA2 splicing, preserves HMGA2 function in the setting of an increase in let-7 miRNA levels, delineating how CLK3 and HMGA2 form a functional axis that influences HSC properties during development. Collectively, our study highlights molecular mechanisms by which alternative splicing and miRNA-mediated post-transcriptional regulation impact the molecular identity and stage-specific developmental features of human HSCs.

Graphical abstract

Teaser

Human hematopoietic stem cells (HSCs) display substantial transcriptional diversity during development. Here, we investigated the contribution of alternative splicing to such diversity by analyzing the dynamics of a key hematopoietic regulator, HMGA2. Next, we showed that CLK3, by regulating the splicing pattern of HMGA2, reinforces an HSC-specific program.


https://ift.tt/2JlJF4y

Human Hippocampal Neurogenesis Persists throughout Aging

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Maura Boldrini, Camille A. Fulmore, Alexandria N. Tartt, Laika R. Simeon, Ina Pavlova, Verica Poposka, Gorazd B. Rosoklija, Aleksandar Stankov, Victoria Arango, Andrew J. Dwork, René Hen, J. John Mann
Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Graphical abstract

Teaser

Boldrini et al. find persistent adult neurogenesis in humans into the eighth decade of life, despite declines in quiescent stem cell pools, angiogenesis, and neuroplasticity. Over a 65-year age span, proliferating neural progenitors, immature and mature granule neurons, glia, and dentate gryus volume were unchanged.


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Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Ryo Yamamoto, Adam C. Wilkinson, Jun Ooehara, Xun Lan, Chen-Yi Lai, Yusuke Nakauchi, Jonathan K. Pritchard, Hiromitsu Nakauchi
Aging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs.

Graphical abstract

Teaser

Yamamoto et al. explore age-related changes to HSC function through large-scale clonal analysis using single-cell transplantation. They find large increases in myeloid-restricted repopulating progenitors (MyRPs) as well as a population of MyRPs that display a broader differentiation capacity only in secondary transplants, suggesting additional mechanisms contributing to hematopoietic aging.


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Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Thomas A. Rando, Fabrisia Ambrosio




https://ift.tt/2GG12eN

Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): H.-H. Greco Song, Rowza T. Rumma, C. Keith Ozaki, Elazer R. Edelman, Christopher S. Chen




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Contrasting congener profiles for persistent organic pollutants and PAH monitoring in European storm petrels ( Hydrobates pelagicus ) breeding in Ireland: a preen oil versus feathers approach

Abstract

Persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs) are anthropogenic contaminants of environmental concern due to their persistence in the environment and capacity to accumulate in biota. Many of these contaminants have been found to have ill effects over wildlife and humans. Birds are known to be particularly affected through endocrine disruption and eggshell thinning. POPs have been banned or restricted through the Stockholm Convention (2001), making monitoring essential for tracking effects of regulation. Seabirds have been used as monitoring tools for being top predators and consuming a diverse array of prey in different trophic levels. Non-destructive sampling has become widely popular using feathers and preen oil, as opposed to carcasses and internal organs. This study aimed to set baseline levels of POP and PAH concentration in a highly pelagic and abundant seabird in Ireland and the Atlantic, the European storm petrel, Hydrobates pelagicus, and to investigate the profiles of contaminant congeners in preen oil and feathers, comparatively. Mean concentrations in preen oil followed: PCB (10.1 ng/g ww) > PAH (7.1 ng/g ww) > OCP (5.4 ng/g ww) > PBDE (3.9 ng/g ww), whilst mean concentrations in feathers followed the order: PAH (38.9 ng/g ww) > PCB (27.2 ng/g ww) > OCP (17.9 ng/g ww) > PBDE (4.5 ng/g ww). Congener profiles highly differed between preen oil and feathers, and little correlation was found between the matrices. These results demonstrate that the sampling of a single matrix alone (preen oil or feathers) might produce confounding results on contamination in seabirds and that more than one matrix is recommended to obtain a full picture of contamination by persistent organic pollutants.

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La tuberculose pseudotumorale, un diagnostic difficile

Publication date: Available online 5 April 2018
Source:Revue des Maladies Respiratoires
Author(s): H. Snene, A. Ben Mansour, S. Toujani, N. Ben Salah, M. Mjid, Y. Ouahchi, N. Mehiri, M. Beji, J. Cherif, B. Louzir
IntroductionLa tuberculose dans sa forme pseudotumorale est une entité rare. Quelle que soit sa localisation, elle peut simuler une néoplasie par sa présentation radiologique et/ou endoscopique. À travers ce travail, nous cherchons à mettre en exergue les difficultés diagnostiques de cette pathologie.MéthodesIl s'agit d'une étude rétrospective menée sur les dossiers de patients hospitalisés de 2003 à 2016, au service de pneumologie de l'hôpital La Rabta, pour tuberculose pseudotumorale thoracique.RésultatsDix-sept patients ont été colligés. L'âge médian était de 41 ans. La symptomatologie était dominée par la toux et le fléchissement de l'état général. Toutes les explorations radiologiques étaient pathologiques dont 10 cas de lésions suspectes. La fibroscopie bronchique avait montré des anomalies endobronchiques dans 11 cas. Le délai diagnostique global médian était de 97jours. Le diagnostic a été confirmé bactériologiquement dans cinq cas, histologiquement dans 14 cas et a été retenu sur des éléments de présomption dans un cas. L'évolution était favorable : 13 patients déclarés guéris et quatre patients sont en cours de traitement.ConclusionLe diagnostic positif de tuberculose pseudotumorale thoracique est difficile. Les prélèvements bactériologiques sont souvent négatifs. Ces difficultés sont à l'origine d'un important retard diagnostique et thérapeutique.IntroductionThe pseudotumorous form of tuberculosis is a rare entity. Whatever its location, it can simulate neoplasia by its radiological and/or endoscopic appearances. We highlight the diagnostic difficulties associated with this type of presentation.MethodsWe performed a retrospective study of inpatient records from 2003 to 2016 in the pneumology department of La Rabta Hospital to identify cases of thoracic tuberculous pseudo-tumor.ResultsSeventeen patients were identified. The median age was 41 years and their symptomatology was dominated by cough and general debility. All had abnormal radiology with 10 cases of suspect lesions. Fibre-optic bronchoscopy revealed endobronchial abnormalities in 11 cases. The median overall diagnostic delay was 97 days. The diagnosis was confirmed bacteriologically in five cases, histologically in 14 cases and based on clinical presumption in one case. The progression was favourable: 13 patients have been declared cured and four patients are still undergoing treatment.ConclusionMaking a positive diagnosis of thoracic tuberculous pseudotumour can be difficult, as bacteriological samples are often negative. This can lead to a significant delay in diagnosis and treatment.



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Intranasal instillation of iron oxide nanoparticles induces inflammation and perturbation of trace elements and neurotransmitters, but not behavioral impairment in rats

Abstract

Over the last decades, engineered nanomaterials have been widely used in various applications due to their interesting properties. Among them, iron oxide nanoparticles (IONPs) are used as theranostic agents for cancer, and also as contrast agents in magnetic resonance imaging. With the increasing production and use of these IONPs, there is an evident raise of IONP exposure and subsequently a higher risk of adverse outcome for humans and the environment. In this work, we aimed to investigate the effects of sub-acute IONP exposure on Wistar rat, particularly (i) on the emotional and learning/memory behavior, (ii) on the hematological and biochemical parameters, (iii) on the neurotransmitter content, and (vi) on the trace element homeostasis. Rats were treated during seven consecutive days by intranasal instillations at a dose of 10 mg/kg body weight. The mean body weight increased significantly in IONP-exposed rats. Moreover, several hematological parameters were normal in treated rats except the platelet count which was increased. The biochemical study revealed that phosphatase alkaline level decreased in IONP-exposed rats, but no changes were observed for the other hepatic enzymes (ALT and AST) levels. The trace element homeostasis was slightly modulated by IONP exposure. Sub-acute intranasal exposure to IONPs increased dopamine and norepinephrine levels in rat brain; however, it did not affect the emotional behavior, the anxiety index, and the learning/memory capacities of rats.

https://ift.tt/2GDI9Nt

Fluorescent in vivo imaging of reactive oxygen species and redox potential in plants

Publication date: Available online 5 April 2018
Source:Free Radical Biology and Medicine
Author(s): Cristina Ortega-Villasante, Stefan Burén, Alfonso Blázquez-Castro, Ángel Barón-Sola, Luis E. Hernández
Reactive oxygen species (ROS) are by-products of aerobic metabolism, and excessive production can result in oxidative stress and cell damage. In addition, ROS function as cellular messengers, working as redox regulators in a multitude of biological processes. Understanding ROS signalling and stress responses requires methods for precise imaging and quantification to monitor local, subcellular and global ROS dynamics with high selectivity, sensitivity and spatiotemporal resolution. In this review, we summarize the present knowledge for in vivo plant ROS imaging and detection, using both chemical probes and fluorescent protein-based biosensors. Certain characteristics of plant tissues, for example high background autofluorescence in photosynthetic organs and the multitude of endogenous antioxidants, can interfere with ROS and redox potential detection, making imaging extra challenging. Novel methods and techniques to measure in vivo plant ROS and redox changes with better selectivity, accuracy, and spatiotemporal resolution are therefore desirable to fully acknowledge the remarkably complex plant ROS signalling networks.

Graphical abstract

https://ift.tt/2GBU7XQ

The Immune Landscape of Cancer

Publication date: Available online 5 April 2018
Source:Immunity
Author(s): Vésteinn Thorsson, David L. Gibbs, Scott D. Brown, Denise Wolf, Dante S. Bortone, Tai-Hsien Ou Yang, Eduard Porta-Pardo, Galen F. Gao, Christopher L. Plaisier, James A. Eddy, Elad Ziv, Aedin C. Culhane, Evan O. Paull, I.K. Ashok Sivakumar, Andrew J. Gentles, Raunaq Malhotra, Farshad Farshidfar, Antonio Colaprico, Joel S. Parker, Lisle E. Mose, Nam Sy Vo, Jianfang Liu, Yuexin Liu, Janet Rader, Varsha Dhankani, Sheila M. Reynolds, Reanne Bowlby, Andrea Califano, Andrew D. Cherniack, Dimitris Anastassiou, Davide Bedognetti, Arvind Rao, Ken Chen, Alexander Krasnitz, Hai Hu, Tathiane M. Malta, Houtan Noushmehr, Chandra Sekhar Pedamallu, Susan Bullman, Akinyemi I. Ojesina, Andrew Lamb, Wanding Zhou, Hui Shen, Toni K. Choueiri, John N. Weinstein, Justin Guinney, Joel Saltz, Robert A. Holt, Charles E. Rabkin, Alexander J. Lazar, Jonathan S. Serody, Elizabeth G. Demicco, Mary L. Disis, Benjamin G. Vincent, llya Shmulevich
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

Graphical abstract

Teaser

Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.


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